U.S. patent application number 11/361599 was filed with the patent office on 2006-09-07 for compounds.
This patent application is currently assigned to Kudos Pharmaceuticals Ltd. Invention is credited to Xiao-Ling Fan Cockcroft, Sylvie Gomez, Marc Geoffrey Hummersone, Keith Allan Menear, Graeme Cameron Murray Smith.
Application Number | 20060199804 11/361599 |
Document ID | / |
Family ID | 34430242 |
Filed Date | 2006-09-07 |
United States Patent
Application |
20060199804 |
Kind Code |
A1 |
Hummersone; Marc Geoffrey ;
et al. |
September 7, 2006 |
Compounds
Abstract
Compounds of formula I: A-B-C (I)and isomers, salts, solvates,
chemically protected forms, and prodrugs thereof wherein: B is
selected from the group consisting of: ##STR1## where R.sup.N is H
or Me; or B is a divalent C.sub.5 heterocyclic residue containing
one or two ring heteroatoms; A is: ##STR2## R.sup.A3 and R.sup.A5
are independently selected from halo, OR.sup.O and R.sup.AC, where
R.sup.O is H or Me, and R.sup.AC is H or C.sub.1-4 alkyl; X.sup.A
is selected from N and CR.sup.A4, where R.sup.A4 is selected from
H, OR.sup.O, CH.sub.2OH, CO.sub.2H, NHSO.sub.2Me and NHCOMe;
R.sup.A2 and R.sup.A6 are independently selected from H, halo and
OR.sup.O; or R.sup.A3 and R.sup.A4 together with the carbon atoms
to which they are attached, or RA2 and R.sup.A3 together with the
carbon atoms to which they are attached, may form a C.sub.5-6
heterocylic or heteroaromatic ring, containing at least one
nitrogen ring atom; where if X is not N, 1, 2, or 3 of R.sup.A2 to
R.sup.A6 are not H; C is: ##STR3## where X is selected from N and
CH, Y is selected from N and CH, and Z is selected from N and
CR.sup.C6; R.sup.C3 is selected from H, halo and an optionally
substituted N-containing C.sub.5-7 heterocyclic group; R.sup.C5 is
a group selected from: ##STR4## which group may be selected by one
or two C.sub.1-4 alkyl groups or a carboxy group; R.sup.C6 is H;
or, when X and Y are N, R.sup.C5 and R.sup.C6 (when Z is CR.sup.C6)
together with the carbon atoms to which they are attached may form
a fused C.sub.6 aromatic ring selected from the group consisting
of: ##STR5##
Inventors: |
Hummersone; Marc Geoffrey;
(Cambridge, GB) ; Gomez; Sylvie; (Cambridge,
GB) ; Menear; Keith Allan; (Cambridge, GB) ;
Cockcroft; Xiao-Ling Fan; (Cambridge, GB) ; Smith;
Graeme Cameron Murray; (Cambridge, GB) |
Correspondence
Address: |
MICHAEL BEST & FRIEDRICH, LLP
ONE SOUTH PINCKNEY STREET
P O BOX 1806
MADISON
WI
53701
US
|
Assignee: |
Kudos Pharmaceuticals Ltd
Cambridge
GB
|
Family ID: |
34430242 |
Appl. No.: |
11/361599 |
Filed: |
February 24, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60656193 |
Feb 25, 2005 |
|
|
|
Current U.S.
Class: |
514/218 ;
514/227.5; 514/235.2; 514/241; 514/275; 514/332; 540/575; 544/112;
544/123; 544/329; 544/60 |
Current CPC
Class: |
C07D 251/54 20130101;
C07D 403/04 20130101; C07D 405/14 20130101; C07D 417/04 20130101;
C07D 471/04 20130101; C07D 401/14 20130101; C07D 403/14 20130101;
C07D 405/04 20130101 |
Class at
Publication: |
514/218 ;
514/241; 514/275; 514/227.5; 514/235.2; 514/332; 540/575; 544/060;
544/112; 544/123; 544/329 |
International
Class: |
A61K 31/551 20060101
A61K031/551; A61K 31/541 20060101 A61K031/541; A61K 31/5377
20060101 A61K031/5377; A61K 31/53 20060101 A61K031/53; A61K 31/506
20060101 A61K031/506; C07D 417/02 20060101 C07D417/02; C07D 413/02
20060101 C07D413/02; C07D 403/02 20060101 C07D403/02 |
Foreign Application Data
Date |
Code |
Application Number |
Feb 25, 2005 |
GB |
0503962.3 |
Claims
1. A compound of formula I: A-B-C (I) and isomers, salts, solvates,
chemically protected forms, and prodrugs thereof wherein: B is
selected from the group consisting of: ##STR253## where R.sup.N is
H or Me; or B is a divalent C.sub.5 heterocyclic residue containing
one or two ring heteroatoms; A is: ##STR254## R.sup.A3 and R.sup.A5
are independently selected from halo, OR.sup.O and R.sup.AC, where
R.sup.O is H or Me, and R.sup.AC is H or C.sub.1-4 alkyl; X.sup.A
is selected from N and CR.sup.A4, where R.sup.A4 is selected from
H, OR.sup.O, CH.sub.2OH, CO.sub.2H, NHSO.sub.2Me and NHCOMe;
R.sup.A2 and R.sup.A6 are independently selected from H, halo and
OR.sup.O; or R.sup.A3 and R.sup.A4 together with the carbon atoms
to which they are attached, or RA2 and R.sup.A3 together with the
carbon atoms to which they are attached, may form a C.sub.5-6
heterocylic or heteroaromatic ring, containing at least one
nitrogen ring atom; where if X is not N, 1, 2, or 3 of R.sup.A2 to
R.sup.A6 are not H; C is: ##STR255## where X is selected from N and
CH, Y is selected from N and CH, and Z is selected from N and
CR.sup.C6; R.sup.C3 is selected from H, halo and an optionally
substituted N-containing C.sub.5-7 heterocyclic group; R.sup.C5 is
a group selected from: ##STR256## which group may be selected by
one or two C.sub.1-4 alkyl groups or a carboxy group; R.sup.C6 is
H; or, when X and Y are N, R.sup.C5 and R.sup.C6 (when Z is
CR.sup.C6) together with the carbon atoms to which they are
attached may form a fused C.sub.6 aromatic ring selected from the
group consisting of: ##STR257## with the proviso that when X and Y
are N and Z is N or CH, R.sup.C3 and R.sup.C5 are both morpholino,
then B is not ##STR258##
2. A compound according to claim 1, wherein A is: ##STR259##
3. A compound according to claim 1, wherein R.sup.AC is methyl.
4. A compound according to claim 1, wherein R.sup.A2 and R.sup.A6
are selected from H and OR.sup.O.
5. A compound according to claim 1, wherein R.sup.A4 is
OR.sup.O.
6. A compound according to claim 1, wherein B is selected from the
group consisting of: ##STR260##
7. A compound according to claim 1, wherein B is not: ##STR261##
when R.sup.N is H.
8. A compound according to claim 1, wherein at least two of X, Y
and Z are N.
9. A compound according to claim 8, wherein all of X, Y and Z are
N.
10. A compound according to claim 1, wherein R.sup.C3 is selected
from morpholino, thiomorpholino, piperadinyl, piperazinyl,
homopiperazinyl and pyrrolidinyl.
11. A compound according to claim 1, wherein R.sup.C5 is
morpholino.
12. A pharmaceutical composition comprising a compound of formula
I: A-B-C (I) and a pharmaceutically acceptable carrier or diluent,
wherein: B is selected from the group consisting of: ##STR262##
where R.sup.N is H or Me; or B is a divalent C.sub.5 heterocyclic
residue containing one or two ring heteroatoms; A is: ##STR263##
R.sup.A3 and R.sup.A5 are independently selected from halo,
OR.sup.O and R.sup.AC, where R.sup.O is H or Me, and R.sup.AC is H
or C.sub.1-4 alkyl; X.sup.A is selected from N and CR.sup.A4, where
R.sup.A4 is selected from H, OR.sup.O, CH.sub.2OH, CO.sub.2H,
NHSO.sub.2Me and NHCOMe; R.sup.A2 and R.sup.A6 are independently
selected from H, halo and OR.sup.O; or R.sup.A3 and R.sup.A4
together with the carbon atoms to which they are attached, or RA2
and R.sup.A3 together with the carbon atoms to which they are
attached, may form a C.sub.5-6 heterocylic or heteroaromatic ring,
containing at least one nitrogen ring atom; where if X is not N, 1,
2, or 3 of R.sup.A2 to R.sup.A6 are not H; C is: ##STR264## where X
is selected from N and CH, Y is selected from N and CH, and Z is
selected from N and CR.sup.C6; R.sup.C3 is selected from H, halo
and an optionally substituted N-containing C.sub.5-7 heterocyclic
group; R.sup.C5 is a group selected from: ##STR265## which group
may be selected by one or two C.sub.1-4 alkyl groups or a carboxy
group; R.sup.C6 is H; or, when X and Y are N, R.sup.C5 and R.sup.C6
(when Z is CR.sup.C6) together with the carbon atoms to which they
are attached may form a fused C.sub.6 aromatic ring selected from
the group consisting of: ##STR266##
13. A composition according to claim 12, wherein A is:
##STR267##
14. A composition according to claim 12, wherein R.sup.AC is
methyl.
15. A composition according to claim 12, wherein R.sup.A2 and
R.sup.A6 are selected from H and OR.sup.O.
16. A composition according to claim 12, wherein R.sup.A4 is
OR.sup.O.
17. A composition according to claim 12, wherein B is selected from
the group consisting of: ##STR268##
18. A composition according to claim 12, wherein B is not:
##STR269## when R.sup.N is H.
19. A composition according to claim 12, wherein at least two of X,
Y and Z are N.
20. A composition according to claim 19, wherein all of X, Y and Z
are N.
21. A composition according to claim 12, wherein R.sup.C3 is
selected from morpholino, thiomorpholino, piperadinyl, piperazinyl,
homopiperazinyl and pyrrolidinyl.
22. A composition according to claim 12, wherein R.sup.C5 is
morpholino.
23. A method of treating a disease ameliorated by the inhibition of
mTOR, comprising administering to a subject in need of treatment a
therapeutically-effective amount of a compound as defined in claim
12, or a pharmaceutically acceptable salt thereof.
24. The method according to claim 23, wherein the disease
ameliorated by the inhibition of mTOR is selected from cancer,
immuno-suppression, immune tolerance, autoimmune disease,
inflammation, bone loss, bowel disorders, hepatic fibrosis, hepatic
necrosis, rheumatoid arthritis, restinosis, cardiac allograft
vasculopathy, psoriasis, beta-thalassaemia, and ocular
conditions.
25. A method of treating cacner, comprising administering to a
subject in need of treatment a therapeutically-effective amount of
a compound as defined in claim 12, or a pharmaceutically acceptable
salt thereof, simultaneously or sequentially with ionizing
radiation or chemotherapeutic agents.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the priority benefit of U.S.
Provisional Patent Application Ser. No. 60/656,193 filed on Feb.
25, 2005 and United Kingdom Patent Application No, 0503962.3 filed
Feb. 25, 2005. These applications are incorporated herein by
reference.
[0002] The present invention relates to compounds which act as mTOR
inhibitors, their use and their synthesis.
BACKGROUND
[0003] Growth factor/mitogenic activation of the
phosphatidylinositol 3-kinase (PI3K)/AKT signalling pathway
ultimately leads to the key cell cycle and growth control regulator
mTOR, the mammalian target of rapamycin (alternatively referred to
as FRAP (FKBP12 and rapamycin associated protein), RAFT1 (rapamycin
and FKBP12 target 1), RAPT1 (rapamycin target 1)--all derived from
the interaction with the FK-506-binding protein FKBP12, and SEP
(sirolimus effector protein)). mTOR is a mammalian serine/threonine
kinase of approximately 289 kDa in size and a member of the
evolutionary conserved eukaryotic TOR kinases (refs. 1-4). The mTOR
protein is a member of the PI3-kinase like kinase (PIKK) family of
proteins due to its C-terminal homology (catalytic domain) with
PI3-kinase and the other family members, e.g. DNA-PKcs (DNA
dependent protein kinase), ATM (Ataxia-telangiectasia mutated). In
addition to a catalytic domain in the C-terminus, mTOR contains a
FKBP12/rapamycin complex binding domain (FRB). At the N-terminus up
to 20 HEAT (Huntingtin, EF3, alpha regulatory subunit of PP2A and
TOR) motifs are found whilst more C-terminal is a FAT
(FRAP-ATM-TRRAP) domain, and at the extreme C-terminus of the
protein an additional FAT domain is found (FAT-C) (refs. 5,6).
[0004] TOR has been identified as a central regulator of both cell
growth (size) and proliferation, which is in part governed by
translation initiation. TOR dependant phosphorylation of S6-kinase
(S6K1) allows translation of ribosomal proteins involved in cell
cycle progression (refs. 7-9). Cap-dependant translation is
regulated by the phosphorylation of the eukaryotic translation
initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1 (PHAS-1)).
This modification prevents PHAS-1 binding eIF4E, thereby permitting
formation of an active eIF4F translation complex (reviewed in refs.
10,11,12). Activation of these signalling elements is dependant on
insulin, other growth factors and nutrients suggesting a gatekeeper
role for mTOR in the control of cell cycle progression only under
favourable environmental conditions. The PI3K/AKT signalling
cascade lies upstream of mTOR and this has been shown to be
deregulated in certain cancers and results in growth factor
independent activation in, for example, PTEN deficient cells. mTOR
lies at the axis of control for this pathway and inhibitors of this
kinase (e.g. sirolimus (rapamycin or Rapamune.TM.) and everolimus
(RAD001 or Certican.TM.)) are already approved for
immunosuppression and drug eluting stents (reviewed in refs. 13,
14), and are now receiving particular interest as novel agents for
cancer treatment.
[0005] Tumour cell growth arises from the deregulation of normal
growth control mechanisms such as the loss of tumour suppressor
function(s). One such tumour suppressor is the phosphatase and
tensin homologue deleted from chromosome ten (PTEN). This gene,
also known as mutated in multiple advanced cancers (MMAC), has been
shown to play a significant role in cell cycle arrest and is the
most highly mutated tumour suppressor after p53. Up to 30% of
glioblastoma, endometrial and prostate cancers have somatic
mutations or deletions of this locus (refs. 15,16).
[0006] PI3K converts phosphatidylinositol 4,5, bisphosphate (PIP2)
to phosphatidylinositol 3,4,5, triphosphate (PIP3) whilst PTEN is
responsible for removing the 3' phosphate from PIP3 producing PIP2.
PI3-K and PTEN act to maintain an appropriate level of PIP3 which
recruits and thus activates AKT (also known as PKB) and the
downstream signalling cascade that is then initiated. In the
absence of PTEN, there is inappropriate regulation of this cascade,
AKT becomes effectively constitutively activated and cell growth is
deregulated. An alternative mechanism for the deregulation of this
cell signalling process is the recent identification of a mutant
form of the PI3K isoform, p110alpha (ref. 17). The apparent
increased activity of this mutant is thought to result in increased
PIP3 production, presumably in excess of that which the function of
PTEN can counteract. Increased signalling from PI3K, thus results
in increased signalling to mTOR and consequently, its downstream
activators.
[0007] In addition to the evidence linking mTOR with cell cycle
regulation (from G1 to S-phase) and that inhibition of mTOR results
in inhibition of these regulatory events it has been shown that
down regulation of mTOR activity results in cell growth inhibition
(Reviewed in refs. 7,18,19). The known inhibitor of mTOR,
rapamycin, potently inhibits proliferation or growth of cells
derived from a range of tissue types such as smooth muscle, T-cells
as well as cells derived from a diverse range of tumour types
including rhabdomyosarcoma, neuroblastoma, glioblastoma and
medulloblastoma, small cell lung cancer, osteosarcoma, pancreatic
carcinoma and breast and prostate carcinoma (reviewed in ref.
20).
[0008] Rapamycin has been approved and is in clinical use as an
immunosuppressant, its prevention of organ rejection being
successful and with fewer side effects than previous therapies
(refs. 20, 21). Inhibition of mTOR by rapamycin and its analogues
(RAD001, CCl-779) is brought about by the prior interaction of the
drug with the FK506 binding protein, FKBP12. Subsequently, the
complex of FKBP12/rapamycin then binds to the FRB domain of mTOR
and inhibits the downstream signalling from mTOR.
[0009] The potent but non-specific inhibitors of PI3K, LY294002 and
wortmannin, also have been shown to inhibit the kinase function of
mTOR but act through targeting the catalytic domain of the protein
(ref. 21). Further to the inhibition of mTOR function by small
molecules targeted to the kinase domain, it has been demonstrated
that kinase dead mTOR cannot transmit the upstream activating
signals to the downstream effectors of mTOR, PHAS-1 or p70S6 kinase
(ref. 22). It is also shown that not all functions of mTOR are
rapamycin sensitive and this may be related to the observation that
rapamycin alters the substrate profile of mTOR rather than
inhibiting its activity per se (ref. 23). Therefore, it is proposed
that a kinase domain directed inhibitor of mTOR may be a more
effective inhibitor of mTOR.
[0010] In addition to rapamycin's ability to induce growth
inhibition (cytostasis) in its own right, rapamycin and its
derivatives have been shown to potentiate the cytotoxicity of a
number of chemotherapies including cisplatin, camptothecin and
doxorubicin (reviewed in ref. 20). Potentiation of ionising
radiation induced cell killing has also been observed following
inhibition of mTOR (ref. 24) Experimental and clinical evidence has
shown that rapamycin analogues are showing evidence of efficacy in
treating cancer, either alone or in combination with other
therapies (see refs. 10,18,20).
[0011] The vast majority of mTOR pharmacology to date has focused
on inhibition of mTOR via rapamycin or its analogues. However, as
noted above, the only non-rapamycin agents that have been reported
to inhibit mTOR's activity via a kinase domain targetted mechanism
are the small molecule LY294002 and the natural product wortmannin
(ref. 21).
SUMMARY OF THE INVENTION
[0012] The present inventors have identified compounds which are
ATP-competitive inhibitors of mTOR, and hence are non-rapamycin
like in their mechanism of action.
[0013] Accordingly, the first aspect of the present invention
provides a compound of formula I: A-B-C (I) and isomers, salts,
solvates, chemically protected forms, and prodrugs thereof wherein:
[0014] B is selected from the group consisting of: ##STR6## [0015]
where R.sup.N is H or Me; [0016] or B is a divalent C.sub.5
heterocyclic residue containing one or two ring heteroatoms; [0017]
A is: ##STR7## [0018] R.sup.A3 and R.sup.A5 are independently
selected from halo, OR.sup.O and R.sup.AC, where R.sup.O is H or
Me, and R.sup.AC is H or C.sub.1-4 alkyl; [0019] X.sup.A is
selected from N and CR.sup.A4, where R.sup.A4 is selected from H,
OR.sup.O, CH.sub.2OH, CO.sub.2H, NHSO.sub.2Me and NHCOMe; [0020]
R.sup.A2 and R.sup.A6 are independently selected from H, halo and
OR.sup.O; [0021] or R.sup.A3 and R.sup.A4 together with the carbon
atoms to which they are attached, or RA2 and R.sup.A3 together with
the carbon atoms to which they are attached, may form a C.sub.5-6
heterocylic or heteroaromatic ring, containing at least one
nitrogen ring atom; [0022] where if X is not N, 1, 2, or 3 of
R.sup.A2 to R.sup.A6 are not H; [0023] C is: ##STR8## [0024] where
X is selected from N and CH, Y is selected from N and CH, and Z is
selected from N and CR.sup.C6; [0025] R.sup.C3 is selected from H,
halo and an optionally substituted N-containing C.sub.5-7
heterocyclic group; [0026] R.sup.C5 is a group selected from:
##STR9## [0027] which group may be selected by one or two C.sub.1-4
alkyl groups or a carboxy group; [0028] R.sup.C6 is H; [0029] or,
when X and Y are N, R.sup.C5 and R.sup.C6 (when Z is CR.sup.C6)
together with the carbon atoms to which they are attached may form
a fused C.sub.6 aromatic ring selected from the group consisting
of: ##STR10## [0030] with the proviso that when X and Y are N and Z
is N or CH, R.sup.C3 and R.sup.C5 are both morpholino, then B is
not ##STR11##
[0031] Therefore when X and Y are N, and R.sup.C5 and R.sup.C6
together with the carbon atoms to which they are attached form a
fused C.sub.6 aromatic ring, then C is either: ##STR12##
[0032] A second aspect of the present invention provides a
pharmaceutical composition comprising a compound of a compound of
formula I: A-B-C (I) and isomers, salts, solvates, chemically
protected forms, and prodrugs thereof wherein: [0033] B is selected
from the group consisting of: ##STR13## [0034] where R.sup.N is H
or Me; [0035] or B is a divalent C.sub.5 heterocyclic residue
containing one or two ring heteroatoms; [0036] A is: ##STR14##
[0037] R.sup.A3 and R.sup.A5 are independently selected from halo,
OR.sup.O and R.sup.AC, where R.sup.O is H or Me, and R.sup.AC is H
or C.sub.1-4 alkyl; [0038] X.sup.A is selected from N and
CR.sup.A4, where R.sup.A4 is selected from H, OR.sup.O, CH.sub.2OH,
CO.sub.2H, NHSO.sub.2Me and NHCOMe; [0039] R.sup.A2 and R.sup.A6
are independently selected from H, halo and OR.sup.O; [0040] or
R.sup.A3 and R.sup.A4 together with the carbon atoms to which they
are attached, or RA2 and R.sup.A3 together with the carbon atoms to
which they are attached, may form a C.sub.5-6 heterocylic or
heteroaromatic ring, containing at least one nitrogen ring atom;
[0041] where if X is not N, 1, 2, or 3 of R.sup.A2 to R.sup.A6 are
not H; [0042] C is: ##STR15## [0043] where X is selected from N and
CH, Y is selected from N and CH, and Z is selected from N and
CR.sup.C6; [0044] R.sup.C3 is selected from H, halo and an
optionally substituted N-containing C.sub.5-7 heterocyclic group;
[0045] R.sup.C5 is a group selected from: ##STR16## [0046] which
group may be selected by one or two C.sub.1-4 alkyl groups or a
carboxy group; [0047] R.sup.C6 is H; [0048] or, when X and Y are N,
R.sup.C5 and R.sup.C6 (when Z is CR.sup.C6) together with the
carbon atoms to which they are attached may form a fused C.sub.6
aromatic ring selected from the group consisting of: ##STR17##
[0049] and a pharmaceutically acceptable carrier or diluent.
[0050] A third aspect of the present invention provides a compound
of the second aspect for use in a method of treatment of the human
or animal body.
[0051] A fourth aspect of the present invention provides the use of
a compound as defined in the second aspect of the invention in the
preparation of a medicament for treating a disease ameliorated by
the inhibition of mTOR.
[0052] Further aspects of the invention provide the use of a
compound as defined in the second aspect of the invention in the
preparation of a medicament for the treatment of: cancer,
immuno-suppression, immune tolerance, autoimmune disease,
inflammation, bone loss, bowel disorders, hepatic fibrosis, hepatic
necrosis, rheumatoid arthritis, restinosis, cardiac allograft
vasculopathy, psoriasis, beta-thalassaemia, and ocular conditions
such as dry eye. mTOR inhibitors may also be effective as
antifungal agents
[0053] Another further aspect of the invention provides for the use
of a compound as defined in the second aspect of the invention in
the preparation of a medicament for use as an adjunct in cancer
therapy or for potentiating tumour cells for treatment with
ionizing radiation or chemotherapeutic agents.
[0054] Other further aspects of the invention provide for the
treatment of disease ameliorated by the inhibition of mTOR,
comprising administering to a subject in need of treatment a
therapeutically-effective amount of a compound as defined in the
second aspect, preferably in the form of a pharmaceutical
composition and the treatment of cancer, comprising administering
to a subject in need of treatment a therapeutically-effective
amount of a compound as defined in the first aspect in combination,
preferably in the form of a pharmaceutical composition,
simultaneously or sequentially with ionizing radiation or
chemotherapeutic agents.
Definitions
[0055] Alkyl: The term "alkyl" as used herein, pertains to a
monovalent moiety obtained by removing a hydrogen atom from a
carbon atom of a hydrocarbon compound having from 1 to 20 carbon
atoms (unless otherwise specified), which may be aliphatic or
alicyclic, and which may be saturated or unsaturated (e.g.
partially unsaturated, fully unsaturated). Thus, the term "alkyl"
includes the sub-classes alkenyl, alkynyl, cycloalkyl,
cycloalkyenyl, cylcoalkynyl, etc., discussed below.
[0056] In the context of alkyl groups, the prefixes (e.g.
C.sub.1-4, C.sub.1-7, C.sub.1-20, C.sub.2-7, C.sub.3-7, etc.)
denote the number of carbon atoms, or range of number of carbon
atoms. For example, the term "C.sub.1-4 alkyl", as used herein,
pertains to an alkyl group having from 1 to 4 carbon atoms.
Examples of groups of alkyl groups include C.sub.1-4 alkyl ("lower
alkyl"), C.sub.1-7 alkyl, and C.sub.1-20 alkyl. Note that the first
prefix may vary according to other limitations; for example, for
unsaturated alkyl groups, the first prefix must be at least 2; for
cyclic alkyl groups, the first prefix must be at least 3; etc.
[0057] Examples of (unsubstituted) saturated alkyl groups include,
but are not limited to, methyl (C.sub.1), ethyl (C.sub.2), propyl
(C.sub.3), butyl (C.sub.4), pentyl (C.sub.5), hexyl (C.sub.6),
heptyl (C.sub.7), octyl (C.sub.8), nonyl (C.sub.9), decyl
(C.sub.10), undecyl (C.sub.11), dodecyl (C.sub.12), tridecyl
(C.sub.13), tetradecyl (C.sub.14), pentadecyl (C.sub.15), and
eicodecyl (C.sub.20).
[0058] Examples of (unsubstituted) saturated linear alkyl groups
include, but are not limited to, methyl (C.sub.1), ethyl (C.sub.2),
n-propyl (C.sub.3), n-butyl (C.sub.4), n-pentyl (amyl) (C.sub.5),
n-hexyl (C.sub.6), and n-heptyl (C.sub.7).
[0059] Examples of (unsubstituted) saturated branched alkyl groups
include iso-propyl (C.sub.3), iso-butyl (C.sub.4), sec-butyl
(C.sub.4), tert-butyl (C.sub.4), iso-pentyl (C.sub.5), and
neo-pentyl (C.sub.5).
[0060] Alkenyl: The term "alkenyl", as used herein, pertains to an
alkyl group having one or more carbon-carbon double bonds. Examples
of groups of alkenyl groups include C.sub.2-4 alkenyl, C.sub.2-7
alkenyl, C.sub.2-20 alkenyl.
[0061] Examples of (unsubstituted) unsaturated alkenyl groups
include, but are not limited to, ethenyl (vinyl,
--CH.dbd.CH.sub.2), 1-propenyl (--CH.dbd.CH--CH.sub.3), 2-propenyl
(allyl, --CH--CH.dbd.CH.sub.2), isopropenyl (1-methylvinyl,
--C(CH.sub.3).dbd.CH.sub.2), butenyl (C.sub.4), pentenyl (C.sub.5),
and hexenyl (C6).
[0062] Alkynyl: The term "alkynyl", as used herein, pertains to an
alkyl group having one or more carbon-carbon triple bonds. Examples
of groups of alkynyl groups include C.sub.2-4 alkynyl, C.sub.2-7
alkynyl, C.sub.2-20 alkynyl.
[0063] Examples of (unsubstituted) unsaturated alkynyl groups
include, but are not limited to, ethynyl (ethinyl, --C.ident.CH)
and 2-propynyl (propargyl, --CH.sub.2--C.ident.CH).
[0064] Cycloalkyl: The term "cycloalkyl", as used herein, pertains
to an alkyl group which is also a cyclyl group; that is, a
monovalent moiety obtained by removing a hydrogen atom from an
alicyclic ring atom of a carbocyclic ring of a carbocyclic
compound, which carbocyclic ring may be saturated or unsaturated
(e.g. partially unsaturated, fully unsaturated), which moiety has
from 3 to 20 carbon atoms (unless otherwise specified), including
from 3 to 20 ring atoms. Thus, the term "cycloalkyl" includes the
sub-classes cycloalkenyl and cycloalkynyl. Preferably, each ring
has from 3 to 7 ring atoms. Examples of groups of cycloalkyl groups
include C.sub.3-20 cycloalkyl, C.sub.3-15 cycloalkyl, C.sub.3-10
cycloalkyl, C.sub.3-7 cycloalkyl.
[0065] Examples of cycloalkyl groups include, but are not limited
to, those derived from: [0066] saturated monocyclic hydrocarbon
compounds: [0067] cyclopropane (C.sub.3), cyclobutane (C.sub.4),
cyclopentane (C.sub.5), cyclohexane (C.sub.6), cycloheptane
(C.sub.7), methylcyclopropane (C.sub.4), dimethylcyclopropane
(C.sub.5), methylcyclobutane (C.sub.5), dimethylcyclobutane
(C.sub.6), methylcyclopentane (C.sub.6), dimethylcyclopentane
(C.sub.7), methylcyclohexane (C.sub.7), dimethylcyclohexane
(C.sub.8), menthane (C.sub.10); [0068] unsaturated monocyclic
hydrocarbon compounds: [0069] cyclopropene (C.sub.3), cyclobutene
(C.sub.4), cyclopentene (C.sub.5), cyclohexene (C.sub.6),
methylcyclopropene (C.sub.4), dimethylcyclopropene (C.sub.5),
methylcyclobutene (C.sub.5), dimethylcyclobutene (C.sub.6),
methylcyclopentene (C.sub.6), dimethylcyclopentene (C.sub.7),
methylcyclohexene (C.sub.7), dimethylcyclohexene (C.sub.8); [0070]
saturated polycyclic hydrocarbon compounds: [0071] thujane
(C.sub.10), carane (C.sub.10), pinane (C.sub.10), bornane
(C.sub.10), norcarane (C.sub.7), norpinane (C.sub.7), norbornane
(C.sub.7), adamantane (C.sub.10), decalin (decahydronaphthalene)
(C.sub.10); [0072] unsaturated polycyclic hydrocarbon compounds:
[0073] camphene (C.sub.10), limonene (C.sub.10), pinene (C.sub.10);
[0074] polycyclic hydrocarbon compounds having an aromatic ring:
[0075] indene (C.sub.9), indane (e.g., 2,3-dihydro-1H-indene)
(C.sub.9), tetraline (1,2,3,4-tetrahydronaphthalene) (C.sub.10),
acenaphthene (C.sub.12), fluorene (C.sub.13), phenalene (C.sub.13),
acephenanthrene (C.sub.15), aceanthrene (C.sub.16), cholanthrene
(C.sub.20).
[0076] Heterocyclyl: The term "heterocyclyl", as used herein,
pertains to a monovalent moiety obtained by removing a hydrogen
atom from a ring atom of a heterocyclic compound, which moiety has
from 3 to 20 ring atoms (unless otherwise specified), of which from
1 to 10 are ring heteroatoms. Preferably, each ring has from 3 to 7
ring atoms, of which from 1 to 4 are ring heteroatoms.
[0077] In this context, the prefixes (e.g. C.sub.3-20, C.sub.3-7,
C.sub.5-6, etc.) denote the number of ring atoms, or range of
number of ring atoms, whether carbon atoms or heteroatoms. For
example, the term "C.sub.5-6heterocyclyl", as used herein, pertains
to a heterocyclyl group having 5 or 6 ring atoms. Examples of
groups of heterocyclyl groups include C.sub.3-20 heterocyclyl,
C.sub.5-20 heterocyclyl, C.sub.3-15 heterocyclyl, C.sub.5-15
heterocyclyl, C.sub.3-12 heterocyclyl, C.sub.5-12 heterocyclyl,
C.sub.3-10 heterocyclyl, C.sub.5-10 heterocyclyl, C.sub.3-7
heterocyclyl, C.sub.5-7 heterocyclyl, and C.sub.5-6
heterocyclyl.
[0078] Examples of monocyclic heterocyclyl groups include, but are
not limited to, those derived from: [0079] N.sub.1: aziridine
(C.sub.3), azetidine (C.sub.4), pyrrolidine (tetrahydropyrrole)
(C.sub.5), pyrroline (e.g., 3-pyrroline, 2,5-dihydropyrrole)
(C.sub.5), 2H-pyrrole or 3H-pyrrole (isopyrrole, isoazole)
(C.sub.5), piperidine (C.sub.6), dihydropyridine (C.sub.6),
tetrahydropyridine (C.sub.6), azepine (C.sub.7); [0080] O.sub.1:
oxirane (C.sub.3), oxetane (C.sub.4), oxolane (tetrahydrofuran)
(C.sub.5), oxole (dihydrofuran) (C.sub.5), oxane (tetrahydropyran)
(C.sub.6), dihydropyran (C.sub.6), pyran (C.sub.6), oxepin
(C.sub.7); [0081] S.sub.1: thiirane (C.sub.3), thietane (C.sub.4),
thiolane (tetrahydrothiophene) (C.sub.5), thiane
(tetrahydrothiopyran) (C.sub.6), thiepane (C.sub.7); [0082]
O.sub.2: dioxolane (C.sub.5), dioxane (C.sub.6), and dioxepane
(C.sub.7); [0083] O.sub.3: trioxane (C.sub.6); [0084] N.sub.2:
imidazolidine (C.sub.5), pyrazolidine (diazolidine) (C.sub.5),
imidazoline (C.sub.5), pyrazoline (dihydropyrazole) (C.sub.5),
piperazine (C.sub.6); [0085] N.sub.1O.sub.1: tetrahydrooxazole
(C.sub.5), dihydrooxazole (C.sub.5), tetrahydroisoxazole (C.sub.5),
dihydroisoxazole (C.sub.5), morpholine (C.sub.6), tetrahydrooxazine
(C.sub.6), dihydrooxazine (C.sub.6), oxazine (C.sub.6); [0086]
N.sub.1S.sub.1: thiazoline (C.sub.5), thiazolidine (C.sub.5),
thiomorpholine (C.sub.6); [0087] N.sub.2O.sub.1: oxadiazine
(C.sub.6); [0088] O.sub.1S.sub.1: oxathiole (C.sub.5) and oxathiane
(thioxane) (C.sub.6); and, [0089] N.sub.1O.sub.1S.sub.1:
oxathiazine (C.sub.6).
[0090] Examples of substituted (non-aromatic) monocyclic
heterocyclyl groups include those derived from saccharides, in
cyclic form, for example, furanoses (C.sub.5), such as
arabinofuranose, lyxofuranose, ribofuranose, and xylofuranse, and
pyranoses (C.sub.6), such as allopyranose, altropyranose,
glucopyranose, mannopyranose, gulopyranose, idopyranose,
galactopyranose, and talopyranose.
[0091] N-containing C.sub.5-7 heterocyclic group: The term
"N-containing C.sub.5-7 heterocyclic group" as used herein refers
to a 5 to 7 membered heterocylic ring containing at least one
nitrogen ring atom. Examples of these groups include, but are not
limited to: [0092] N.sub.1: pyrrolidine (tetrahydropyrrole)
(C.sub.5), pyrroline (e.g., 3-pyrroline, 2,5-dihydropyrrole)
(C.sub.5), 2H-pyrrole or 3H-pyrrole (isopyrrole, isoazole)
(C.sub.5), piperidine (C.sub.6), dihydropyridine (C.sub.6),
tetrahydropyridine (C.sub.6), azepine (C.sub.7); [0093] N.sub.2:
imidazolidine (C.sub.5), pyrazolidine (diazolidine) (C.sub.5),
imidazoline (C.sub.5), pyrazoline (dihydropyrazole) (C.sub.5),
piperazine (C.sub.6); [0094] N.sub.1O.sub.1: tetrahydrooxazole
(C.sub.5), dihydrooxazole (C.sub.5), tetrahydroisoxazole (C.sub.5),
dihydroisoxazole (C.sub.5), morpholine (C.sub.6), tetrahydrooxazine
(C.sub.6), dihydrooxazine (C.sub.6), oxazine (C.sub.6); [0095]
N.sub.1S.sub.1: thiazoline (C.sub.5), thiazolidine (C.sub.5),
thiomorpholine (C.sub.6); [0096] N.sub.2O.sub.1: oxadiazine
(C.sub.6); [0097] N.sub.1O.sub.1S.sub.1: oxathiazine (C.sub.6).
[0098] Divalent C.sub.5 heterocyclic residue: The term "divalent
C.sub.5 heterocyclic residue" as used herein, refers to a divalent
moiety obtained by removing two hydrogen atoms from ring atoms of a
heterocyclic compound, which moiety has 5 ring atoms. These
residues have one or two ring heteroatoms. They can be derived from
the groups list above as C5 heterocyclic groups.
[0099] Spiro-C.sub.3-7 cycloalkyl or heterocyclyl: The term "spiro
C.sub.3-7 cycloalkyl or heterocyclyl" as used herein, refers to a
C.sub.3-7 cycloalkyl or C.sub.3-7 heterocyclyl ring joined to
another ring by a single atom common to both rings.
[0100] C.sub.5-20 aryl: The term "C.sub.5-20 aryl" as used herein,
pertains to a monovalent moiety obtained by removing a hydrogen
atom from an aromatic ring atom of a C.sub.5-20 aromatic compound,
said compound having one ring, or two or more rings (e.g., fused),
and having from 5 to 20 ring atoms, and wherein at least one of
said ring(s) is an aromatic ring. Preferably, each ring has from 5
to 7 ring atoms.
[0101] The ring atoms may be all carbon atoms, as in "carboaryl
groups" in which case the group may conveniently be referred to as
a "C.sub.5-20 carboaryl" group.
[0102] Examples of C.sub.5-20 aryl groups which do not have ring
heteroatoms (i.e. C.sub.5-20 carboaryl groups) include, but are not
limited to, those derived from benzene (i.e. phenyl) (C.sub.6),
naphthalene (C.sub.10), anthracene (C.sub.14), phenanthrene
(C.sub.14), and pyrene (C.sub.16).
[0103] Alternatively, the ring atoms may include one or more
heteroatoms, including but not limited to oxygen, nitrogen, and
sulfur, as in "heteroaryl groups". In this case, the group may
conveniently be referred to as a "C.sub.5-20 heteroaryl" group,
wherein "C.sub.5-20" denotes ring atoms, whether carbon atoms or
heteroatoms. Preferably, each ring has from 5 to 7 ring atoms, of
which from 0 to 4 are ring heteroatoms.
[0104] Examples of C.sub.5-20 heteroaryl groups include, but are
not limited to, C.sub.5 heteroaryl groups derived from furan
(oxole), thiophene (thiole), pyrrole (azole), imidazole
(1,3-diazole), pyrazole (1,2-diazole), triazole, oxazole,
isoxazole, thiazole, isothiazole, oxadiazole, tetrazole and
oxatriazole; and C.sub.6 heteroaryl groups derived from isoxazine,
pyridine (azine), pyridazine (1,2-diazine), pyrimidine
(1,3-diazine; e.g., cytosine, thymine, uracil), pyrazine
(1,4-diazine) and triazine.
[0105] The heteroaryl group may be bonded via a carbon or hetero
ring atom.
[0106] Examples of C.sub.5-20 heteroaryl groups which comprise
fused rings, include, but are not limited to, C.sub.9heteroaryl
groups derived from benzofuran, isobenzofuran, benzothiophene,
indole, isoindole; C.sub.10 heteroaryl groups derived from
quinoline, isoquinoline, benzodiazine, pyridopyridine; C.sub.14
heteroaryl groups derived from acridine and xanthene.
[0107] C.sub.5-6 heterocyclic or heteroaromatic ring: The term
"C.sub.5-6 heterocyclic or heteroaromatic ring" as used herein
refers to a ring which has either 5 or 6 ring atoms, and which may
be fully saturated, partially unsaturated or aromatic. The ring may
be one of those listed above from which C.sub.5-6 heterocyclic and
heteroaryl groups are derived from.
[0108] The above alkyl, heterocyclyl, and aryl groups, whether
alone or part of another substituent, may themselves optionally be
substituted with one or more groups selected from themselves and
the additional substituents listed below.
[0109] Halo: --F, --Cl, --Br, and --I.
[0110] Hydroxy: --OH.
[0111] Ether: --OR, wherein R is an ether substituent, for example,
a C.sub.1-7 alkyl group (also referred to as a C.sub.1-7 alkoxy
group), a C.sub.3-20 heterocyclyl group (also referred to as a
C.sub.3-20 heterocyclyloxy group), or a C.sub.5-20 aryl group (also
referred to as a C.sub.5-20 aryloxy group), preferably a C.sub.1-7
alkyl group.
[0112] Nitro: --NO.sub.2.
[0113] Cyano (nitrile, carbonitrile): --CN.
[0114] Acyl (keto): --C(.dbd.O)R, wherein R is an acyl substituent,
for example, H, a C.sub.1-7 alkyl group (also referred to as
C.sub.1-7 alkylacyl or C.sub.1-7 alkanoyl), a C.sub.3-20
heterocyclyl group (also referred to as C.sub.3-20
heterocyclylacyl), or a C.sub.5-20 aryl group (also referred to as
C.sub.5-20 arylacyl), preferably a C.sub.1-7 alkyl group. Examples
of acyl groups include, but are not limited to, --C(.dbd.O)CH.sub.3
(acetyl), --C(.dbd.O)CH.sub.2CH.sub.3 (propionyl),
--C(.dbd.O)C(CH.sub.3).sub.3 (butyryl), and --C(.dbd.O)Ph (benzoyl,
phenone).
[0115] Carboxy (carboxylic acid): --COOH.
[0116] Ester (carboxylate, carboxylic acid ester, oxycarbonyl):
--C(.dbd.O)OR, wherein R is an ester substituent, for example, a
C.sub.1-7 alkyl group, a C.sub.3-20 heterocyclyl group, or a
C.sub.5-20 aryl group, preferably a C.sub.1-7 alkyl group. Examples
of ester groups include, but are not limited to,
--C(.dbd.O)OCH.sub.3, --C(.dbd.O)OCH.sub.2CH.sub.3,
--C(.dbd.O)OC(CH.sub.3).sub.3, and --C(.dbd.O)OPh.
[0117] Amido (carbamoyl, carbamyl, aminocarbonyl, carboxamide):
--C(.dbd.O)NR.sup.1R.sup.2, wherein R.sup.1 and R.sup.2 are
independently amino substituents, as defined for amino groups.
Examples of amido groups include, but are not limited to,
--C(.dbd.O)NH.sub.2, --C(.dbd.O)NHCH.sub.3,
--C(.dbd.O)N(CH.sub.3).sub.2, --C(.dbd.O)NHCH.sub.2CH.sub.3, and
--C(.dbd.O)N(CH.sub.2CH.sub.3).sub.2, as well as amido groups in
which R.sup.1 and R.sup.2, together with the nitrogen atom to which
they are attached, form a heterocyclic structure as in, for
example, piperidinocarbonyl, morpholinocarbonyl,
thiomorpholinocarbonyl, and piperazinylcarbonyl.
[0118] Amino: --NR.sup.1R.sup.2, wherein R.sup.1 and R.sup.2 are
independently amino substituents, for example, hydrogen, a
C.sub.1-7 alkyl group (also referred to as C.sub.1-7 alkylamino or
di-C.sub.1-7 alkylamino), a C.sub.3-20 heterocyclyl group, or a
C.sub.5-20 aryl group, preferably H or a C.sub.1-7 alkyl group, or,
in the case of a "cyclic" amino group, R.sup.1 and R.sup.2, taken
together with the nitrogen atom to which they are attached, form a
heterocyclic ring having from 4 to 8 ring atoms. Examples of amino
groups include, but are not limited to, --NH.sub.2, --NHCH.sub.3,
--NHCH(CH.sub.3).sub.2, --N(CH.sub.3).sub.2,
--N(CH.sub.2CH.sub.3).sub.2, and --NHPh. Examples of cyclic amino
groups include, but are not limited to, aziridinyl, azetidinyl,
pyrrolidinyl, piperidino, piperazinyl, perhydrodiazepinyl,
morpholino, and thiomorpholino. The cylic amino groups may be
substituted on their ring by any of the substituents defined here,
for example carboxy, carboxylate and amido.
[0119] Acylamido (acylamino): --NR.sup.1C(.dbd.O)R.sup.2, wherein
R.sup.1 is an amide substituent, for example, hydrogen, a C.sub.1-7
alkyl group, a C.sub.3-20 heterocyclyl group, or a C.sub.5-20 aryl
group, preferably H or a C.sub.1-7 alkyl group, most preferably H,
and R.sup.2 is an acyl substituent, for example, a C.sub.1-7 alkyl
group, a C.sub.3-20 heterocyclyl group, or a C.sub.5-20 aryl group,
preferably a C.sub.1-7 alkyl group. Examples of acylamide groups
include, but are not limited to, --NHC(.dbd.O)CH.sub.3,
--NHC(.dbd.O)CH.sub.2CH.sub.3, and --NHC(.dbd.O)Ph. R.sup.1 and
R.sup.2 may together form a cyclic structure, as in, for example,
succinimidyl, maleimidyl, and phthalimidyl: ##STR18##
[0120] Ureido: --N(R.sup.1)CONR.sup.2R.sup.3 wherein R.sup.2 and
R.sup.3 are independently amino substituents, as defined for amino
groups, and R1 is a ureido substituent, for example, hydrogen, a
C.sub.1-7alkyl group, a C.sub.3-20heterocyclyl group, or a
C.sub.5-20aryl group, preferably hydrogen or a C.sub.1-7alkyl
group. Examples of ureido groups include, but are not limited to,
--NHCONH.sub.2, --NHCONHMe, --NHCONHEt, --NHCONMe.sub.2,
--NHCONEt.sub.2, --NMeCONH.sub.2, --NMeCONHMe, --NMeCONHEt,
--NMeCONMe.sub.2, --NMeCONEt.sub.2 and --NHC(.dbd.O)NHPh.
[0121] Acyloxy (reverse ester): --OC(.dbd.O)R, wherein R is an
acyloxy substituent, for example, a C.sub.1-7 alkyl group, a
C.sub.3-20 heterocyclyl group, or a C.sub.5-20 aryl group,
preferably a C.sub.1-7 alkyl group. Examples of acyloxy groups
include, but are not limited to, --OC(.dbd.O)CH.sub.3 (acetoxy),
--OC(.dbd.O)CH.sub.2CH.sub.3, --OC(.dbd.O)C(CH.sub.3).sub.3,
--OC(.dbd.O)Ph, --OC(.dbd.O)C.sub.6H.sub.4F, and
--OC(.dbd.O)CH.sub.2Ph.
[0122] Thiol : --SH.
[0123] Thioether (sulfide): --SR, wherein R is a thioether
substituent, for example, a C.sub.1-7 alkyl group (also referred to
as a C.sub.1-7 alkylthio group), a C.sub.3-20 heterocyclyl group,
or a C.sub.5-20 aryl group, preferably a C.sub.1-7 alkyl group.
Examples of C.sub.1-7 alkylthio groups include, but are not limited
to, --SCH.sub.3 and --SCH.sub.2CH.sub.3.
[0124] Sulfoxide (sulfinyl): --S(.dbd.O)R, wherein R is a sulfoxide
substituent, for example, a C.sub.1-7 alkyl group, a C.sub.3-20
heterocyclyl group, or a C.sub.5-20 aryl group, preferably a
C.sub.1-7 alkyl group. Examples of sulfoxide groups include, but
are not limited to, --S(.dbd.O)CH.sub.3 and
--S(.dbd.O)CH.sub.2CH.sub.3.
[0125] Sulfonyl (sulfone): --S(.dbd.O).sub.2R, wherein R is a
sulfone substituent, for example, a C.sub.1-7 alkyl group, a
C.sub.3-20 heterocyclyl group, or a C.sub.5-20 aryl group,
preferably a C.sub.1-7 alkyl group. Examples of sulfone groups
include, but are not limited to, --S(.dbd.O).sub.2CH.sub.3
(methanesulfonyl, mesyl), --S(.dbd.O).sub.2CF.sub.3,
--S(.dbd.O).sub.2CH.sub.2CH.sub.3, and 4-methylphenylsulfonyl
(tosyl).
[0126] Thioamido (thiocarbamyl): --C(.dbd.S)NR.sup.1R.sup.2,
wherein R.sup.1 and R.sup.2 are independently amino substituents,
as defined for amino groups. Examples of amido groups include, but
are not limited to, --C(.dbd.S)NH.sub.2, --C(.dbd.S)NHCH.sub.3,
--C(.dbd.S)N(CH.sub.3).sub.2, and
--C(.dbd.S)NHCH.sub.2CH.sub.3.
[0127] Sulfonamino: --NR.sup.1S(.dbd.O).sub.2R, wherein R.sup.1 is
an amino substituent, as defined for amino groups, and R is a
sulfonamino substituent, for example, a C.sub.1-7alkyl group, a
C.sub.3-20heterocyclyl group, or a C.sub.5-20aryl group, preferably
a C.sub.1-7alkyl group. Examples of sulfonamino groups include, but
are not limited to, --NHS(.dbd.O).sub.2CH.sub.3,
--NHS(.dbd.O).sub.2Ph and
--N(CH.sub.3)S(.dbd.O).sub.2C.sub.6H.sub.5.
[0128] As mentioned above, the groups that form the above listed
substituent groups, e.g. C.sub.1-7 alkyl, C.sub.3-20 heterocyclyl
and C.sub.5-20 aryl, may themselves be substituted. Thus, the above
definitions cover substituent groups which are substituted.
Further Preferences
[0129] The following preferences can apply to each aspect of the
present invention, where applicable. The preferences for each group
may be combined with those for any or all of the other groups, as
appropriate.
[0130] The proviso that when X and Y are N and Z is N or CH,
R.sup.C3 and R.sup.C5 are both morpholino, then B is not ##STR19##
may apply to any aspect of the present invention.
[0131] A
[0132] A is preferably: ##STR20## where R.sup.A2 to R.sup.A6 are as
defined above.
[0133] Where R.sup.A3 and R.sup.A4 together with the carbon atoms
to which they are attached, or R.sup.A2 and R.sup.A3 together with
the carbon atoms to which they are attached, form a C.sub.5-6
heterocylic or heteroaromatic ring, containing at least one
nitrogen ring atom and the ring is aromatic then exemplary groups
include, but are not limited to, pyridine, pyrrole (e.g. azole),
imidazole (e.g. 1H-imidazole), triazole (e.g. 1-Me-triazole). If
the ring is not aromatic, it may be oxazolone.
[0134] R.sup.AC may be selected from methyl and t-butyl, and in
some embodiments is preferably methyl.
[0135] It may be preferred that R.sup.A4 is only H, when R.sup.A3
and R.sup.A5 are OH.
[0136] R.sup.A2 and R.sup.A6 may preferably be selected from H and
OR.sup.O.
[0137] In some embodiments, A is: ##STR21## [0138] where R.sup.A3
and R.sup.A5 are independently selected from halo, OR.sup.O and
R.sup.O, where R.sup.O is H or Me; [0139] R.sup.A4 is selected from
OR.sup.O, CO.sub.2H, NHSO.sub.2Me and NHCOMe; or, when R.sup.A3 and
R.sup.A5 are OH, [0140] R.sup.A4 may be H; [0141] R.sup.A2 and
R.sup.A6 are independently selected from H and OR.sup.O; [0142]
where 1, 2, or 3 of R.sup.A2 to R.sup.A6 are not H.
[0143] It is preferred that 2 or 3 of R.sup.A2 to R.sup.A6 are not
H, and it is more preferred that 3 of R.sup.A2 to R.sup.A6 are not
H. Those of R.sup.A2 to R.sup.A6 which are not H are preferably
OR.sup.O, and more preferably OH.
[0144] It is preferred that R.sup.A4 is OR.sup.O, and more
particularly OH.
[0145] R.sup.A3 and R.sup.A5 are preferably independently selected
from H and OR.sup.O, and more preferably selected from H and
OH.
[0146] R.sup.A2 and R.sup.A6 are preferably independently selected
from H and OH.
[0147] Preferred A groups are: 2,3,4-trihydoxy phenyl;
3,4,5-trihydroxy phenyl; 2,4,6-trihydoxy phenyl; 3,4-dihydroxy
phenyl; and 3,5-dimethoxy, 4-hydroxy phenyl.
[0148] B
[0149] If B is a divalent C.sub.5 heterocyclic residue, it is
preferred that the ring atoms bound to A and C are separated by a
further ring atom. It may be preferred that at least one ring atom
is nitrogen, in which case, it is further preferred that there are
two ring heteroatoms, the second being selected from nitrogen and
sulphur. If there is only a single ring heteroatom, this is
preferably selected from oxygen and sulphur.
[0150] B may be selected from the group consisting of:
##STR22##
[0151] In some embodiments, B may be selected from the group
consisting of: ##STR23## ##STR24##
[0152] In some aspects of the invention, it is preferred that B is
not: ##STR25## where R.sup.N is H.
[0153] It may be preferred that B is not ##STR26## where R.sup.N is
as defined for formula I.
[0154] B is preferably selected from the group consisting of:
##STR27## where R.sup.N is H or Me, and is preferably H.
[0155] B is preferably selected from: ##STR28##
[0156] C
[0157] If X and Y are N, and R.sup.C5 and R.sup.C6 together with
the carbon atoms to which they are attached form a fused C.sub.6
aromatic ring, then C may be selected from: ##STR29##
[0158] If X and Y are N, and R.sup.C5 and R.sup.C6 together with
the carbon atoms to which they are attached form a fused C.sub.6
aromatic ring, then R.sup.C3 is preferably H, and C is more
preferably: ##STR30##
[0159] It is preferred that at least two of X, Y and Z are N, and
more preferred that all of X, Y and Z are N.
[0160] If two of X, Y and Z are N, then it is preferred that Z and
one of X and Y is N. It is more preferred for Z and Y to be N.
[0161] When less than 3 of X, Y and Z are N, it is preferred that
R.sup.C3 is selected from H and an optionally substituted
N-containing C.sub.5-6 heterocyclic group.
[0162] Preferred optionally substituted N-containing C.sub.5-7
heterocyclic groups for R.sup.C3 include, but are not limited, to
morpholino, thiomorpholino, piperadinyl, piperazinyl (preferably
N-substituted), homopiperazinyl (preferably N-substituted) and
pyrrolidinyl.
[0163] Preferred N-substituents for the piperazinyl and
homopiperazinyl groups include esters, in particular, esters
bearing a C.sub.1-7 alkyl group as an ester substituent, e.g.
--C(.dbd.O)OCH.sub.3, --C(.dbd.O)OCH.sub.2CH.sub.3 and
--C(.dbd.O)OC(CH.sub.3).sub.3.
[0164] More preferred N-containing C.sub.5-7 heterocyclic groups
are morpholino and piperadinyl, with morpholino being the most
preferred. These groups are preferably unsubstituted.
[0165] Preferred groups for R.sup.C5 include those where R.sup.O is
H.
[0166] A particularly preferred group for R.sup.C5 is morpholino,
which in some embodiments is preferably substituted, and in other
embodiments is preferably unsubstituted.
Includes other Forms
[0167] Included in the above are the well known ionic, salt,
solvate, and protected forms of these substituents. For example, a
reference to carboxylic acid (--COOH) also includes the anionic
(carboxylate) form (--COO.sup.-), a salt or solvate thereof, as
well as conventional protected forms. Similarly, a reference to an
amino group includes the protonated form
(--N.sup.+HR.sup.1R.sup.2), a salt or solvate of the amino group,
for example, a hydrochloride salt, as well as conventional
protected forms of an amino group. Similarly, a reference to a
hydroxyl group also includes the anionic form (--O.sup.-), a salt
or solvate thereof, as well as conventional protected forms of a
hydroxyl group.
Isomers, Salts, Solvates, Protected Forms, and Prodrugs
[0168] Certain compounds may exist in one or more particular
geometric, optical, enantiomeric, diasteriomeric, epimeric,
stereoisomeric, tautomeric, conformational, or anomeric forms,
including but not limited to, cis- and trans-forms; E- and Z-forms;
c-, t-, and r-forms; endo- and exo-forms; R-, S-, and meso-forms;
D- and L-forms; d- and l-forms; (+) and (-) forms; keto-, enol-,
and enolate-forms; syn- and anti-forms; synclinal- and
anticlinal-forms; .alpha.- and .beta.-forms; axial and equatorial
forms; boat-, chair-, twist-, envelope-, and halfchair-forms; and
combinations thereof, hereinafter collectively referred to as
"isomers" (or "isomeric forms").
[0169] If the compound is in crystalline form, it may exist in a
number of different polymorphic forms.
[0170] Note that, except as discussed below for tautomeric forms,
specifically excluded from the term "isomers", as used herein, are
structural (or constitutional) isomers (i.e. isomers which differ
in the connections between atoms rather than merely by the position
of atoms in space). For example, a reference to a methoxy group,
--OCH.sub.3, is not to be construed as a reference to its
structural isomer, a hydroxymethyl group, --CH.sub.2OH. Similarly,
a reference to ortho-chlorophenyl is not to be construed as a
reference to its structural isomer, meta-chlorophenyl. However, a
reference to a class of structures may well include structurally
isomeric forms falling within that class (e.g., C.sub.1-7 alkyl
includes n-propyl and iso-propyl; butyl includes n-, iso-, sec-,
and tert-butyl; methoxyphenyl includes ortho-, meta-, and
para-methoxyphenyl).
[0171] The above exclusion does not pertain to tautomeric forms,
for example, keto-, enol-, and enolate-forms, as in, for example,
the following tautomeric pairs: keto/enol, imine/enamine,
amide/imino alcohol, amidine/amidine, nitroso/oxime,
thioketone/enethiol, N-nitroso/hyroxyazo, and nitro/aci-nitro.
[0172] Note that specifically included in the term "isomer" are
compounds with one or more isotopic substitutions. For example, H
may be in any isotopic form, including .sup.1H, .sup.2H (D), and
.sup.3H (T); C may be in any isotopic form, including .sup.12C,
.sup.13C, and .sup.14C; O may be in any isotopic form, including
.sup.16O and .sup.18O; and the like.
[0173] Unless otherwise specified, a reference to a particular
compound includes all such isomeric forms, including (wholly or
partially) racemic and other mixtures thereof.
[0174] Methods for the preparation (e.g. asymmetric synthesis) and
separation (e.g. fractional crystallisation and chromatographic
means) of such isomeric forms are either known in the art or are
readily obtained by adapting the methods taught herein, or known
methods, in a known manner.
[0175] Unless otherwise specified, a reference to a particular
compound also includes ionic, salt, solvate, and protected forms of
thereof, for example, as discussed below, as well as its different
polymorphic forms.
[0176] It may be convenient or desirable to prepare, purify, and/or
handle a corresponding salt of the active compound, for example, a
pharmaceutically-acceptable salt. Examples of pharmaceutically
acceptable salts are discussed in ref. 25.
[0177] For example, if the compound is anionic, or has a functional
group which may be anionic (e.g., --COOH may be --COO.sup.-), then
a salt may be formed with a suitable cation. Examples of suitable
inorganic cations include, but are not limited to, alkali metal
ions such as Na.sup.+ and K.sup.+, alkaline earth cations such as
Ca.sup.2+ and Mg.sup.2+, and other cations such as Al.sup.3+.
Examples of suitable organic cations include, but are not limited
to, ammonium ion (i.e., NH.sub.4.sup.+) and substituted ammonium
ions (e.g., NH.sub.3R.sup.+, NH.sub.2R.sub.2.sup.+,
NHR.sub.3.sup.+, NR.sub.4.sup.+). Examples of some suitable
substituted ammonium ions are those derived from: ethylamine,
diethylamine, dicyclohexylamine, triethylamine, butylamine,
ethylenediamine, ethanolamine, diethanolamine, piperazine,
benzylamine, phenylbenzylamine, choline, meglumine, and
tromethamine, as well as amino acids, such as lysine and arginine.
An example of a common quaternary ammonium ion is
N(CH.sub.3).sub.4.sup.+.
[0178] If the compound is cationic, or has a functional group which
may be cationic (e.g., --NH.sub.2 may be --NH.sub.3.sup.+), then a
salt may be formed with a suitable anion. Examples of suitable
inorganic anions include, but are not limited to, those derived
from the following inorganic acids: hydrochloric, hydrobromic,
hydroiodic, sulfuric, sulfurous, nitric, nitrous, phosphoric, and
phosphorous. Examples of suitable organic anions include, but are
not limited to, those derived from the following organic acids:
acetic, propionic, succinic, gycolic, stearic, palmitic, lactic,
malic, pamoic, tartaric, citric, gluconic, ascorbic, maleic,
hydroxymaleic, phenylacetic, glutamic, aspartic, benzoic, cinnamic,
pyruvic, salicyclic, sulfanilic, 2-acetyoxybenzoic, fumaric,
toluenesulfonic, methanesulfonic, ethanesulfonic, ethane
disulfonic, oxalic, isethionic, valeric, and gluconic. Examples of
suitable polymeric anions include, but are not limited to, those
derived from the following polymeric acids: tannic acid,
carboxymethyl cellulose.
[0179] It may be convenient or desirable to prepare, purify, and/or
handle a corresponding solvate of the active compound. The term
"solvate" is used herein in the conventional sense to refer to a
complex of solute (e.g. active compound, salt of active compound)
and solvent. If the solvent is water, the solvate may be
conveniently referred to as a hydrate, for example, a mono-hydrate,
a di-hydrate, a tri-hydrate, etc.
[0180] It may be convenient or desirable to prepare, purify, and/or
handle the active compound in a chemically protected form. The term
"chemically protected form," as used herein, pertains to a compound
in which one or more reactive functional groups are protected from
undesirable chemical reactions, that is, are in the form of a
protected or protecting group (also known as a masked or masking
group or a blocked or blocking group). By protecting a reactive
functional group, reactions involving other unprotected reactive
functional groups can be performed, without affecting the protected
group; the protecting group may be removed, usually in a subsequent
step, without substantially affecting the remainder of the
molecule. See, for example, ref. 26.
[0181] For example, a hydroxy group may be protected as an ether
(--OR) or an ester (--OC(.dbd.O)R), for example, as: a t-butyl
ether; a benzyl, benzhydryl (diphenylmethyl), or trityl
(triphenylmethyl) ether; a trimethylsilyl or t-butyldimethylsilyl
ether; or an acetyl ester (--OC(.dbd.O)CH.sub.3, --OAc).
[0182] For example, an aldehyde or ketone group may be protected as
an acetal or ketal, respectively, in which the carbonyl group
(>C.dbd.O) is converted to a diether (>C(OR).sub.2), by
reaction with, for example, a primary alcohol. The aldehyde or
ketone group is readily regenerated by hydrolysis using a large
excess of water in the presence of acid.
[0183] For example, an amine group may be protected, for example,
as an amide or a urethane, for example, as: a methyl amide
(--NHCO--CH.sub.3); a benzyloxy amide
(--NHCO--OCH.sub.2C.sub.6H.sub.5, --NH-Cbz); as a t-butoxy amide
(--NHCO--OC(CH.sub.3).sub.3, --NH-Boc); a 2-biphenyl-2-propoxy
amide (--NHCO--OC(CH.sub.3).sub.2C.sub.6H.sub.4C.sub.6H.sub.5,
--NH-Bpoc), as a 9-fluorenylmethoxy amide (--NH-Fmoc), as a
6-nitroveratryloxy amide (--NH-Nvoc), as a 2-trimethylsilylethyloxy
amide (--NH-Teoc); as a 2,2,2-trichloroethyloxy amide (--NH-Troc),
as an allyloxy amide (--NH-Alloc), as a 2(-phenylsulphonyl)ethyloxy
amide (--NH-Psec); or, in suitable cases, as an N-oxide
(>NO.).
[0184] For example, a carboxylic acid group may be protected as an
ester for example, as: an C.sub.1-7 alkyl ester (e.g. a methyl
ester; a t-butyl ester); a C.sub.1-7 haloalkyl ester (e.g. a
C.sub.1-7 trihaloalkyl ester); a triC.sub.1-7 alkylsilyl-C.sub.1-7
alkyl ester; or a C.sub.5-20 aryl-C.sub.1-7 alkyl ester (e.g. a
benzyl ester; a nitrobenzyl ester); or as an amide, for example, as
a methyl amide.
[0185] For example, a thiol group may be protected as a thioether
(--SR), for example, as: a benzyl thioether; an acetamidomethyl
ether (--S--CH.sub.2NHC(.dbd.O)CH.sub.3).
[0186] It may be convenient or desirable to prepare, purify, and/or
handle the active compound in the form of a prodrug. The term
"prodrug", as used herein, pertains to a compound which, when
metabolised (e.g. in vivo), yields the desired active compound.
Typically, the prodrug is inactive, or less active than the active
compound, but may provide advantageous handling, administration, or
metabolic properties.
[0187] For example, some prodrugs are esters of the active compound
(e.g. a physiologically acceptable metabolically labile ester).
During metabolism, the ester group (--C(.dbd.O)OR) is cleaved to
yield the active drug. Such esters may be formed by esterification,
for example, of any of the carboxylic acid groups (--C(.dbd.O)OH)
in the parent compound, with, where appropriate, prior protection
of any other reactive groups present in the parent compound,
followed by deprotection if required. Examples of such
metabolically labile esters include those wherein R is C.sub.1-20
alkyl (e.g. -Me, -Et); C.sub.1-7 aminoalkyl (e.g. aminoethyl;
2-(N,N-diethylamino)ethyl; 2-(4-morpholino)ethyl); and
acyloxy-C.sub.1-7 alkyl (e.g. acyloxymethyl; acyloxyethyl; e.g.
pivaloyloxymethyl; acetoxymethyl; 1-acetoxyethyl;
1-(1-methoxy-1-methyl)ethyl-carbonxyloxyethyl; 1-(benzoyloxy)ethyl;
isopropoxy-carbonyloxymethyl; 1-isopropoxy-carbonyloxyethyl;
cyclohexyl-carbonyloxymethyl; 1-cyclohexyl-carbonyloxyethyl;
cyclohexyloxy-carbonyloxymethyl; 1-cyclohexyloxy-carbonyloxyethyl;
(4-tetrahydropyranyloxy) carbonyloxymethyl;
1-(4-tetrahydropyranyloxy)carbonyloxyethyl;
(4-tetrahydropyranyl)carbonyloxymethyl; and
1-(4-tetrahydropyranyl)carbonyloxyethyl).
[0188] Further suitable prodrug forms include phosphonate and
glycolate salts. In particular, hydroxy groups (--OH), can be made
into phosphonate prodrugs by reaction with chlorodibenzylphosphite,
followed by hydrogenation, to form a phosphonate group
--O--P(.dbd.O)(OH).sub.2. Such a group can be cleared by
phosphotase enzymes during metabolism to yield the active drug with
the hydroxy group.
[0189] Also, some prodrugs are activated enzymatically to yield the
active compound, or a compound which, upon further chemical
reaction, yields the active compound. For example, the prodrug may
be a sugar derivative or other glycoside conjugate, or may be an
amino acid ester derivative.
Acronyms
[0190] For convenience, many chemical moieties are represented
using well known abbreviations, including but not limited to,
methyl (Me), ethyl (Et), n-propyl (nPr), iso-propyl (iPr), n-butyl
(nBu), tert-butyl (tBu), n-hexyl (nHex), cyclohexyl (cHex), phenyl
(Ph), biphenyl (biPh), benzyl (Bn), naphthyl (naph), methoxy (MeO),
ethoxy (EtO), benzoyl (Bz), and acetyl (Ac).
[0191] For convenience, many chemical compounds are represented
using well known abbreviations, including but not limited to,
methanol (MeOH), ethanol (EtOH), iso-propanol (i-PrOH), methyl
ethyl ketone (MEK), ether or diethyl ether (Et.sub.2O), acetic acid
(AcOH), dichloromethane (methylene chloride, DCM), trifluoroacetic
acid (TFA), dimethylformamide (DMF), tetrahydrofuran (THF), and
dimethylsulfoxide (DMSO).
General Synthesis
[0192] When B is selected from: ##STR31## compounds of formula I
may be represented as Formula 1a: ##STR32## where B' represents the
two possible B groups.
[0193] Where B' is: ##STR33## compounds of Formula 1a may be
synthesised by coupling a compound of Formula 2: ##STR34## with a
compound of Formula 3: H.sub.2B'-C Formula 3 in the presence of a
catalytic amount of p-toluenesulfonic acid, or a similar
compound.
[0194] Where B' is: ##STR35## compounds of Formula 1a may be
synthesised by coupling a compound of Formula 4: ##STR36## with a
compound of Formula 3: H.sub.2B'-C Formula 3 in the presence of an
amide coupling agent, such as
O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate.
[0195] Compounds of Formula 3 may be synthesised may be synthesised
from a compound of Formula 5: Cl--C Formula 5 by the addition of
hydrazine hydrate or methyl hydrazine in an organic solvent.
Microwave heating may be used as an alternative to conventional
heating.
[0196] Compounds of Formula 5 where C is: ##STR37## where X is N or
CH, can be represented by Formula 5a: ##STR38##
[0197] Compounds of Formula 5a where R.sup.C3 is an optionally
substituted N-containing C.sub.5-7 heterocyclic group can be
synthesised from a compound of Formula 5a where R.sup.C3 is halo,
e.g. Cl, by reacting them with an appropriate amine. Such compounds
can be synthesised from a compound where R.sup.C5 is halo, e.g. Cl,
in a similar manner. If R.sup.C3 and R.sup.C5 are the formed from
the same amine, these steps are preferably carried out
simultaneously.
[0198] The synthesis of compounds of Formula 5, where C is:
##STR39## are illustrated in Examples 4, 5 and 15 below, which
methods can be adapted to introduce an R.sup.C3 group as
appropriate.
[0199] When C is: ##STR40## and B is: ##STR41## compounds of
Formula 3: H.sub.2B'-C Formula 3 may be represented as Formula 3a:
##STR42## which may be synthesised from a compound of Formula 6:
##STR43## by reaction with sodium nitrite and tin (II) chloride
dihydrate Compounds of Formula 6 can be readily synthesised using
known methods.
[0200] When B is a divalent C.sub.5 heterocyclic residue containing
one or two ring heteroatoms compounds of formula I may be
represented as Formula 1b: A-B''-C Formula 1b where B'' represents
the possible B groups.
[0201] Compounds of Formula 1b where A is: ##STR44## may be
synthesised from compounds of Formula 1b where A is Br--, by
coupling an appropriate boronic acid or ester, using Suzuki
conditions.
[0202] Compounds of Formula 1b where A is Br--, may be synthesised
from compounds of Formula 5: Cl--C Formula 5 by addition of a
compound of Formula 7: Br-B'' Formula 7 with sodium hydride in an
appropriate organic solvent.
[0203] Alternatively a precursor of a compound of Formula 5 may be
coupled to a compound of Formula 7, and then the final
transformation of group C carried out, before continuing the
synthesis.
Use
[0204] The present invention provides active compounds,
specifically, active in inhibiting the activity of mTOR.
[0205] The term "active" as used herein, pertains to compounds
which are capable of inhibiting mTOR activity, and specifically
includes both compounds with intrinsic activity (drugs) as well as
prodrugs of such compounds, which prodrugs may themselves exhibit
little or no intrinsic activity.
[0206] One assay which may conveniently be used in order to assess
the mTOR inhibition offered by a particular compound is described
in the examples below.
[0207] The present invention further provides a method of
inhibiting the activity of mTOR in a cell, comprising contacting
said cell with an effective amount of an active compound,
preferably in the form of a pharmaceutically acceptable
composition. Such a method may be practised in vitro or in
vivo.
[0208] For example, a sample of cells may be grown in vitro and an
active compound brought into contact with said cells, and the
effect of the compound on those cells observed. As examples of
"effect", the inhibition of cellular growth in a certain time or
the accumulation of cells in the G1 phase of the cell cycle over a
certain time may be determined. Where the active compound is found
to exert an influence on the cells, this may be used as a
prognostic or diagnostic marker of the efficacy of the compound in
methods of treating a patient carrying cells of the same cellular
type.
[0209] The term "treatment", as used herein in the context of
treating a condition, pertains generally to treatment and therapy,
whether of a human or an animal (e.g. in veterinary applications),
in which some desired therapeutic effect is achieved, for example,
the inhibition of the progress of the condition, and includes a
reduction in the rate of progress, a halt in the rate of progress,
amelioration of the condition, and cure of the condition. Treatment
as a prophylactic measure (i.e. prophylaxis) is also included.
[0210] The term "adjunct" as used herein relates to the use of
active compounds in conjunction with known therapeutic means. Such
means include cytotoxic regimes of drugs and/or ionising radiation
as used in the treatment of different cancer types. Examples of
adjunct anti-cancer agents that could be combined with compounds
from the invention include, but are not limited to, the following:
alkylating agents: nitrogen mustards, mechlorethamine,
cyclophosphamide, ifosfamide, melphalan, chlorambucil:
Nitrosoureas: carmustine (BCNU), lomustine (CCNU), semustine
(methyl-CCNU), ethylenimine/methylmelamine, thriethylenemelamine
(TEM), triethylene thiophosphoramide (thiotepa), hexamethylmelamine
(HMM, altretamine): Alkyl sufonates; busulfan; Triazines,
dacarbazine (DTIC): Antimetabolites; folic acid analogs,
methotrexate, trimetrexate, pyrimidine analogs, 5-fluorouracil,
fluorodeoxyuridine, gemcitabine, cytosine arabinoside (AraC,
cytarabine), 5-azacytidine, 2,2'-difluorodeoxycytidine: Purine
analogs; 6-mercaptopurine, 6-thioguanine, azathioprine,
2'-deoxycoformycin (pentostatin, erythrohydroxynonyladenine (EHNA),
fludarabine phosphate, 2-Chlorodeoxyadenosine (cladribine, 2-CdA):
Topoisomerase I inhibitors; camptothecin, topotecan, irinotecan,
rubitecan: Natural products; antimitotic drugs, paclitaxel, vinca
alkaloids, vinblastine (VLB), vincristine, vinorelbine,
Taxotere.TM. (docetaxel), estramustine, estramustine phosphate;
epipodophylotoxins, etoposide, teniposide: Antibiotics; actimomycin
D, daunomycin (rubidomycin), doxorubicin (adriamycin),
mitoxantrone, idarubicin, bleomycins, plicamycin (mithramycin),
mitomycin C, dactinomycin: Enzymes; L-asparaginase, RNAse A:
Biological response modifiers; interferon-alpha, IL-2, G-CSF,
GM-CSF: Differentiation Agents; retinoic acid derivatives:
Radiosensitizers;, metronidazole, misonidazole,
desmethylmisonidazole, pimonidazole, etanidazole, nimorazole, RSU
1069, EO9, RB 6145, SR4233, nicotinamide, 5-bromodeozyuridine,
5-iododeoxyuridine, bromodeoxycytidine: Platinium coordination
complexes; cisplatin, carboplatin: Anthracenedione; mitoxantrone,
AQ4N Substituted urea, hydroxyurea; Methylhydrazine derivatives,
N-methylhydrazine (MIH), procarbazine; Adrenocortical suppressant,
mitotane (o.p'-DDD), aminoglutethimide: Cytokines; interferon
(.alpha., .beta., .gamma.), interleukin; Hormones and antagonists;
adrenocorticosteroids/antagonists, prednisone and equivalents,
dexamethasone, aminoglutethimide; Progestins, hydroxyprogesterone
caproate, medroxyprogesterone acetate, megestrol acetate;
Estrogens, diethylstilbestrol, ethynyl estradiol/equivalents;
Antiestrogen, tamoxifen; Androgens, testosterone propionate,
fluoxymesterone/equivalents; Antiandrogens, flutamide,
gonadotropin-releasing hormone analogs, leuprolide; Nonsteroidal
antiandrogens, flutamide; EGFR inhibitors, VEGF inhibitors;
Proteasome inhibitors.
[0211] Active compounds may also be used as cell culture additives
to inhibit mTOR, for example, in order to sensitize cells to known
chemotherapeutic agents or ionising radiation treatments in
vitro.
[0212] Active compounds may also be used as part of an in vitro
assay, for example, in order to determine whether a candidate host
is likely to benefit from treatment with the compound in
question.
Cancer
[0213] The present invention provides active compounds which are
anticancer agents or adjuncts for treating cancer. One of ordinary
skill in the art is readily able to determine whether or not a
candidate compound treats a cancerous condition for any particular
cell type, either alone or in combination.
[0214] Examples of cancers include, but are not limited to, lung
cancer, small cell lung cancer, gastrointestinal cancer, bowel
cancer, colon cancer, breast carinoma, ovarian carcinoma, prostate
cancer, testicular cancer, liver cancer, kidney cancer, bladder
cancer, pancreas cancer, brain cancer, sarcoma, osteosarcoma,
Kaposi's sarcoma, melanoma and leukemias.
[0215] Any type of cell may be treated, including but not limited
to, lung, gastrointestinal (including, e.g., bowel, colon), breast
(mammary), ovarian, prostate, liver (hepatic), kidney (renal),
bladder, pancreas, brain, and skin.
Administration
[0216] The active compound or pharmaceutical composition comprising
the active compound may be administered to a subject by any
convenient route of administration, whether
systemically/peripherally or at the site of desired action,
including but not limited to, oral (e.g. by ingestion); topical
(including e.g. transdermal, intranasal, ocular, buccal, and
sublingual); pulmonary (e.g. by inhalation or insufflation therapy
using, e.g. an aerosol, e.g. through mouth or nose); rectal;
vaginal; parenteral, for example, by injection, including
subcutaneous, intradermal, intramuscular, intravenous,
intraarterial, intracardiac, intrathecal, intraspinal,
intracapsular, subcapsular, intraorbital, intraperitoneal,
intratracheal, subcuticular, intraarticular, subarachnoid, and
intrasternal; by implant of a depot, for example, subcutaneously or
intramuscularly.
[0217] The subject may be a eukaryote, an animal, a vertebrate
animal, a mammal, a rodent (e.g. a guinea pig, a hamster, a rat, a
mouse), murine (e.g. a mouse), canine (e.g. a dog), feline (e.g. a
cat), equine (e.g. a horse), a primate, simian (e.g. a monkey or
ape), a monkey (e.g. marmoset, baboon), an ape (e.g. gorilla,
chimpanzee, orangutang, gibbon), or a human.
Formulations
[0218] While it is possible for the active compound to be
administered alone, it is preferable to present it as a
pharmaceutical composition (e.g., formulation) comprising at least
one active compound, as defined above, together with one or more
pharmaceutically acceptable carriers, adjuvants, excipients,
diluents, fillers, buffers, stabilisers, preservatives, lubricants,
or other materials well known to those skilled in the art and
optionally other therapeutic or prophylactic agents.
[0219] Thus, the present invention further provides pharmaceutical
compositions, as defined above, and methods of making a
pharmaceutical composition comprising admixing at least one active
compound, as defined above, together with one or more
pharmaceutically acceptable carriers, excipients, buffers,
adjuvants, stabilisers, or other materials, as described
herein.
[0220] The term "pharmaceutically acceptable" as used herein
pertains to compounds, materials, compositions, and/or dosage forms
which are, within the scope of sound medical judgement, suitable
for use in contact with the tissues of a subject (e.g. human)
without excessive toxicity, irritation, allergic response, or other
problem or complication, commensurate with a reasonable
benefit/risk ratio. Each carrier, excipient, etc. must also be
"acceptable" in the sense of being compatible with the other
ingredients of the formulation.
[0221] Suitable carriers, diluents, excipients, etc. can be found
in standard pharmaceutical texts. See, for example, refs. 27 to
29.
[0222] The formulations may conveniently be presented in unit
dosage form and may be prepared by any methods well known in the
art of pharmacy. Such methods include the step of bringing into
association the active compound with the carrier which constitutes
one or more accessory ingredients. In general, the formulations are
prepared by uniformly and intimately bringing into association the
active compound with liquid carriers or finely divided solid
carriers or both, and then if necessary shaping the product.
[0223] Formulations may be in the form of liquids, solutions,
suspensions, emulsions, elixirs, syrups, tablets, losenges,
granules, powders, capsules, cachets, pills, ampoules,
suppositories, pessaries, ointments, gels, pastes, creams, sprays,
mists, foams, lotions, oils, boluses, electuaries, or aerosols.
[0224] Formulations suitable for oral administration (e.g., by
ingestion) may be presented as discrete units such as capsules,
cachets or tablets, each containing a predetermined amount of the
active compound; as a powder or granules; as a solution or
suspension in an aqueous or non-aqueous liquid; or as an
oil-in-water liquid emulsion or a water-in-oil liquid emulsion; as
a bolus; as an electuary; or as a paste.
[0225] A tablet may be made by conventional means, e.g. compression
or molding, optionally with one or more accessory ingredients.
Compressed tablets may be prepared by compressing in a suitable
machine the active compound in a free-flowing form such as a powder
or granules, optionally mixed with one or more binders (e.g.
povidone, gelatin, acacia, sorbitol, tragacanth,
hydroxypropylmethyl cellulose); fillers or diluents (e.g. lactose,
microcrystalline cellulose, calcium hydrogen phosphate); lubricants
(e.g. magnesium stearate, talc, silica); disintegrants (e.g. sodium
starch glycolate, cross-linked povidone, cross-linked sodium
carboxymethyl cellulose); surface-active or dispersing or wetting
agents (e.g., sodium lauryl sulfate); and preservatives (e.g.,
methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, sorbic acid).
Molded tablets may be made by molding in a suitable machine a
mixture of the powdered compound moistened with an inert liquid
diluent. The tablets may optionally be coated or scored and may be
formulated so as to provide slow or controlled release of the
active compound therein using, for example, hydroxypropylmethyl
cellulose in varying proportions to provide the desired release
profile. Tablets may optionally be provided with an enteric
coating, to provide release in parts of the gut other than the
stomach.
[0226] Formulations suitable for topical administration (e.g.
transdermal, intranasal, ocular, buccal, and sublingual) may be
formulated as an ointment, cream, suspension, lotion, powder,
solution, past, gel, spray, aerosol, or oil. Alternatively, a
formulation may comprise a patch or a dressing such as a bandage or
adhesive plaster impregnated with active compounds and optionally
one or more excipients or diluents.
[0227] Formulations suitable for topical administration in the
mouth include losenges comprising the active compound in a flavored
basis, usually sucrose and acacia or tragacanth; pastilles
comprising the active compound in an inert basis such as gelatin
and glycerin, or sucrose and acacia; and mouthwashes comprising the
active compound in a suitable liquid carrier.
[0228] Formulations suitable for topical administration to the eye
also include eye drops wherein the active compound is dissolved or
suspended in a suitable carrier, especially an aqueous solvent for
the active compound.
[0229] Formulations suitable for nasal administration, wherein the
carrier is a solid, include a coarse powder having a particle size,
for example, in the range of about 20 to about 500 microns which is
administered in the manner in which snuff is taken, i.e. by rapid
inhalation through the nasal passage from a container of the powder
held close up to the nose. Suitable formulations wherein the
carrier is a liquid for administration as, for example, nasal
spray, nasal drops, or by aerosol administration by nebuliser,
include aqueous or oily solutions of the active compound.
[0230] Formulations suitable for administration by inhalation
include those presented as an aerosol spray from a pressurised
pack, with the use of a suitable propellant, such as
dichlorodifluoromethane, trichlorofluoromethane,
dichoro-tetrafluoroethane, carbon dioxide, or other suitable
gases.
[0231] Formulations suitable for topical administration via the
skin include ointments, creams, and emulsions. When formulated in
an ointment, the active compound may optionally be employed with
either a paraffinic or a water-miscible ointment base.
Alternatively, the active compounds may be formulated in a cream
with an oil-in-water cream base. If desired, the aqueous phase of
the cream base may include, for example, at least about 30% w/w of
a polyhydric alcohol, i.e., an alcohol having two or more hydroxyl
groups such as propylene glycol, butane-1,3-diol, mannitol,
sorbitol, glycerol and polyethylene glycol and mixtures thereof.
The topical formulations may desirably include a compound which
enhances absorption or penetration of the active compound through
the skin or other affected areas. Examples of such dermal
penetration enhancers include dimethylsulfoxide and related
analogues.
[0232] When formulated as a topical emulsion, the oily phase may
optionally comprise merely an emulsifier (otherwise known as an
emulgent), or it may comprises a mixture of at least one emulsifier
with a fat or an oil or with both a fat and an oil. Preferably, a
hydrophilic emulsifier is included together with a lipophilic
emulsifier which acts as a stabiliser. It is also preferred to
include both an oil and a fat. Together, the emulsifier(s) with or
without stabiliser(s) make up the so-called emulsifying wax, and
the wax together with the oil and/or fat make up the so-called
emulsifying ointment base which forms the oily dispersed phase of
the cream formulations.
[0233] Suitable emulgents and emulsion stabilisers include Tween
60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl
monostearate and sodium lauryl sulphate. The choice of suitable
oils or fats for the formulation is based on achieving the desired
cosmetic properties, since the solubility of the active compound in
most oils likely to be used in pharmaceutical emulsion formulations
may be very low. Thus the cream should preferably be a non-greasy,
non-staining and washable product with suitable consistency to
avoid leakage from tubes or other containers. Straight or branched
chain, mono- or dibasic alkyl esters such as di-isoadipate,
isocetyl stearate, propylene glycol diester of coconut fatty acids,
isopropyl myristate, decyl oleate, isopropyl palmitate, butyl
stearate, 2-ethylhexyl palmitate or a blend of branched chain
esters known as Crodamol CAP may be used, the last three being
preferred esters. These may be used alone or in combination
depending on the properties required. Alternatively, high melting
point lipids such as white soft paraffin and/or liquid paraffin or
other mineral oils can be used.
[0234] Formulations suitable for rectal administration may be
presented as a suppository with a suitable base comprising, for
example, cocoa butter or a salicylate.
[0235] Formulations suitable for vaginal administration may be
presented as pessaries, tampons, creams, gels, pastes, foams or
spray formulations containing in addition to the active compound,
such carriers as are known in the art to be appropriate.
[0236] Formulations suitable for parenteral administration (e.g.,
by injection, including cutaneous, subcutaneous, intramuscular,
intravenous and intradermal), include aqueous and non-aqueous
isotonic, pyrogen-free, sterile injection solutions which may
contain anti-oxidants, buffers, preservatives, stabilisers,
bacteriostats, and solutes which render the formulation isotonic
with the blood of the intended recipient; and aqueous and
non-aqueous sterile suspensions which may include suspending agents
and thickening agents, and liposomes or other microparticulate
systems which are designed to target the compound to blood
components or one or more organs. Examples of suitable isotonic
vehicles for use in such formulations include Sodium Chloride
Injection, Ringer's Solution, or Lactated Ringer's Injection.
Typically, the concentration of the active compound in the solution
is from about 1 ng/ml to about 10 .mu.g/ml, for example from about
10 ng/ml to about 1 .mu.g/ml. The formulations may be presented in
unit-dose or multi-dose sealed containers, for example, ampoules
and vials, and may be stored in a freeze-dried (lyophilised)
condition requiring only the addition of the sterile liquid
carrier, for example water for injections, immediately prior to
use. Extemporaneous injection solutions and suspensions may be
prepared from sterile powders, granules, and tablets. Formulations
may be in the form of liposomes or other microparticulate systems
which are designed to target the active compound to blood
components or one or more organs.
Dosage
[0237] It will be appreciated that appropriate dosages of the
active compounds, and compositions comprising the active compounds,
can vary from patient to patient. Determining the optimal dosage
will generally involve the balancing of the level of therapeutic
benefit against any risk or deleterious side effects of the
treatments of the present invention. The selected dosage level will
depend on a variety of factors including, but not limited to, the
activity of the particular compound, the route of administration,
the time of administration, the rate of excretion of the compound,
the duration of the treatment, other drugs, compounds, and/or
materials used in combination, and the age, sex, weight, condition,
general health, and prior medical history of the patient. The
amount of compound and route of administration will ultimately be
at the discretion of the physician, although generally the dosage
will be to achieve local concentrations at the site of action which
achieve the desired effect without causing substantial harmful or
deleterious side-effects.
[0238] Administration in vivo can be effected in one dose,
continuously or intermittently (e.g., in divided doses at
appropriate intervals) throughout the course of treatment. Methods
of determining the most effective means and dosage of
administration are well known to those of skill in the art and will
vary with the formulation used for therapy, the purpose of the
therapy, the target cell being treated, and the subject being
treated. Single or multiple administrations can be carried out with
the dose level and pattern being selected by the treating
physician.
[0239] In general, a suitable dose of the active compound is in the
range of about 100 .mu.g to about 250 mg per kilogram body weight
of the subject per day. Where the active compound is a salt, an
ester, prodrug, or the like, the amount administered is calculated
on the basis of the parent compound and so the actual weight to be
used is increased proportionately.
EXAMPLES
General Experimental Methods
[0240] Thin Layer chromatography was carried out using Merck
Kieselgel 60 F.sub.254 glass backed plates. The plates were
visualized by the use of a UV lamp (254 nm). Silica gel 60
(particle sizes 40-63 .mu.m) supplied by E.M. Merck was employed
for flash chromatography. .sup.1H NMR spectra were recorded at 300
MHz on a Bruker DPX-300 instrument. Chemical shifts were referenced
relative to tetramethylsilane.
Purification and Identification of Library Samples
[0241] The samples were purified on Gilson LC units. Mobile phase
A--0.1% aqueous TFA, mobile phase B--Acetonitrile; flow rate 6
ml/min; Gradient--typically starting at 90% A/10% B for 1 minute,
rising to 97% after 15 minutes, holding for 2 minutes, then back to
the starting conditions. Column: Jones Chromatography Genesis 4
.mu.m, C18 column, 10 mm.times.250 mm. Peak acquisition based on UV
detection at 254 nm.
[0242] Mass spectra were recorded on a Finnegan LCQ instrument in
positive ion mode. Mobile phase A--0.1% aqueous formic acid. Mobile
phase B--Acetonitrile; Flowrate 2 ml/min; Gradient--starting at 95%
A/5% B for 1 minute, rising to 98% B after 5 minutes and holding
for 3 minutes before returning to the starting conditions. Column:
Varies, but always C18 50 mm.times.4.6 mm (currently Genesis C18 4
.mu.m. Jones Chromatography). PDA detection Waters 996, scan range
210-400 nm.
Microwave Synthesis
[0243] Reactions were carried out using a Personal Chemistry.TM.
Emrys Optimiser microwave synthesis unit with robotic arm. Power
range between. 0-300 W at 2.45 GHz. Pressure range between 0-20
bar; temperature increase between 2-5.degree. C./sec; temp range
60-250.degree. C.
Example 1a
Synthesis of 6-(N'-Methylene-hydrazino)-[1,3,5]triazine-2,4-diamine
derivatives (5)
[0244] ##STR45## (i) Synthesis of
4,6-Dichloro-[1,3,5]triazin-2-ylamine Derivatives (2)
[0245] To a cooled (-60.degree. C.) solution of cyanuric chloride
(1)(3.00 g, 16.26 mmol) in ethyleneglycol dimethylether (40 ml) was
added a solution of the appropriate amine (2.80 ml, 32.5 mmol) in
water (1.4 ml). The amine solution was added in a dropwise manner
over the period of 10 minutes. The mixture was removed from the
cooling bath and water added which fully quenched (25 ml) the
reaction. The quenched mixture was stirred for 5 minutes before
being filtered to remove any precipitate. The filter cake was
washed with water (250 ml) and dried in a vacuum desiccator to give
the desired 4,6-dichloro-[1,3,5]triazin-2-ylamine which was then
purified further by recrystallisation from the minimum amount of
hot EtOAc to give the product. TABLE-US-00001 Yield m/z RT Compound
NRR' % [M + H].sup.+ (mins) 2a ##STR46## 35 236 0.64
(iia) Synthesis of 6-Chloro-[1,3,5]triazine-2,4-diamine Derivatives
(3) (where Amine Groups Different)
[0246] To a cooled (-50.degree. C.) solution of appropriate
4,6-dichloro-[1,3,5]triazin-2-yl amine (2)(0.35 mmol) in
dimethylformamide (5 ml) was added powdered K.sub.2CO.sub.3 (1.14
mmol) and then the appropriate amine (0.35 mmol) was added in a
dropwise manner. The mixture was stirred at -50.degree. C. for 10
mins and then allowed to warm slowly to room temperature. Ethyl
acetate (10 ml) and water (10 ml) was added to the reaction
mixture. The organic extract was removed, washed with saturated
brine solution, dried (MgSO.sub.4), filtered and concentrated in
vacuo to typically give a crystalline solid as the desired product
in a suitably pure form to be used without any further
purification. TABLE-US-00002 Com- Yield m/z RT pound NRR' NR''R'''
% [M + H].sup.+ (mins) 3a ##STR47## ##STR48## 52 284 4.90
(iib) Synthesis of 6-Chloro-[1,3,5]triazine-2,4-diamine Derivatives
(3) (where Amine Groups Same)
[0247] To a cooled (0.degree. C.) solution of cyanuric chloride
(1)(3 g, 16.3 mmol) in acetone (50 ml) was added a solution of the
appropriate amine (68.7 mmol) in water (2.99 ml). The solution
became turbid white as a precipitate formed immediately. The
reaction was maintained at 0.degree. C. for 80 minutes whereupon
more water was added to the mixture (100 ml) and the solid removed
by filtration. The filtercake was washed with cold water (50 ml)
and dried in a vacuum desiccator to typically give a white solid as
the desired product in a suitably pure form to be used without any
further purification. TABLE-US-00003 Yield m/z RT Compound NRR'
NR''R''' % [M + H].sup.+ (mins) 3b ##STR49## ##STR50## 78 286
5.69
(iii) Synthesis of 6-Hydrazino-[1,3,5]triazine-2,4-diamine
derivatives (4)
[0248] (a) To a suspension of the appropriate
6-chloro-[1,3,5]triazine-2,4-diamine (3)(20 mmol) in ethanol (25
ml) was added hydrazine hydrate (5 ml, 100 mmol). The mixture was
then heated to reflux and maintained at this temperature for 3
hours. After this time the mixture was cooled to room temperature
where the solid was filtered and washed with ethanol (2.times.20
ml) to give the desired product as a white crystalline solid that
was suitably pure to be used without any further purification
[0249] (b) A suspension of the appropriate
6-chloro-[1,3,5]triazine-2,4-diamine (3)(3.5 mmol) in methyl
hydrazine (5 ml) was heated to reflux for 5 hours. The mixture was
then cooled to 0.degree. C. and water (10 ml) added. The resulting
precipitate was then removed from the mixture by filtration and
washed with water (2.times.10 ml) to give the title compound as a
colourless solid that was suitably clean to be used without any
further purification. TABLE-US-00004 Yield m/z RT Compound NRR'
NR''R''' R'''' % [M + H].sup.+ (mins) 4a ##STR51## ##STR52## H 98
282 2.91 4b ##STR53## ##STR54## Me 99 296 3.04 4c ##STR55##
##STR56## H 66 280 3.28 4d ##STR57## ##STR58## Me 50 294 3.29
(iv) Synthesis of
6-(N'-Methylene-hydrazino)-[1,3,5]triazine-2,4-diamine derivatives
(5)
[0250] (a) To a mixture of the appropriate
6-hydrazino-[1,3,5]triazine-2,4-diamine derivative (4)(0.71 mmol)
in ethanol (4 ml) was added the appropriate aldehyde (0.71 mmol)
and catalytic p-toluenesulfonic acid (0.04 mmol, 4.3 mg). The
mixture was heated under the influence of microwave radiation to
130.degree. C. for 600 seconds (fixed hold time, pre-stirred for 20
seconds. Upon further cooling (0.degree. C.) a precipitate formed
which was removed by suction filtration. The filter cake was then
washed with ice cold ethanol (5 ml) to give the desired
product.
[0251] (b) To a solution of the appropriate
6-hydrazino-[1,3,5]triazine-2,4-diamine derivative (4)(0.50 mmol)
in ethanol (2 ml) was added the appropriate aldehyde (0.50 mmol)
and catalytic p-toluenesulfonic acid (0.036 mmol, 6.1 mg). The
mixture was then cooled (0.degree. C.) which caused a precipitate
to form. The solid was removed by suction filtration and washed
with ice cold ethanol (5 ml) to give the desired product.
TABLE-US-00005 Purity m/z RT NRR' NR''R''' R'''' Ar % [M + H].sup.+
(mins) 5a ##STR59## ##STR60## H ##STR61## 99 418 3.28 5b ##STR62##
##STR63## H ##STR64## 90 418 3.64 5c ##STR65## ##STR66## H
##STR67## 99 544 4.51 5d ##STR68## ##STR69## H ##STR70## 100 416
3.46 5e ##STR71## ##STR72## H ##STR73## 88 418 3.65 5f ##STR74##
##STR75## H ##STR76## 94 402 3.38 5g ##STR77## ##STR78## H
##STR79## 99 414 3.65 5h ##STR80## ##STR81## H ##STR82## 100 386
3.36 5i ##STR83## ##STR84## H ##STR85## 97 463 3.54 5j ##STR86##
##STR87## H ##STR88## 100 400 3.72 5k ##STR89## ##STR90## H
##STR91## 97 427 3.36 5l ##STR92## ##STR93## Me ##STR94## 100 432
4.08 5m ##STR95## ##STR96## Me ##STR97## 98 432 3.28 5n ##STR98##
##STR99## Me ##STR100## 100 416 3.4 5o ##STR101## ##STR102## Me
##STR103## 96 432 3.98 5p ##STR104## ##STR105## Me ##STR106## 100
416 3.4 5q ##STR107## ##STR108## Me ##STR109## 97 460 3.5 5r
##STR110## ##STR111## H ##STR112## 98 444 3.68 5s ##STR113##
##STR114## H ##STR115## 99 498 4.60 5t ##STR116## ##STR117## Me
##STR118## 100 432 3.89 5u ##STR119## ##STR120## H ##STR121## 95
245.5 3.40 5v ##STR122## ##STR123## H ##STR124## 85 410.4 2.38 5w
##STR125## ##STR126## H ##STR127## 90 427.0 2.75 5x ##STR128##
##STR129## H ##STR130## 100 414 3.52
Example 1(b)
Synthesis of
4-[(4-Chloro-6-morpholin-4-yl-[1,3,5]triazin-2-yl)-hydrazonomethyl]-2,6-d-
imethoxy-phenol (7)
[0252] ##STR131## (i)
(4-Chloro-6-morpholin-4-yl-[1,3,5]triazin-2-yl)-hydrazine (6)
[0253] This was synthesized from (2a) using the method of Example
1a(iii) to give a yield of 99%. M/Z (LC-MS, ESP): 231 [M+H].sup.+,
R/T=2.93 mins.
(ii)
4-[(4-Chloro-6-morpholin-4-yl-[1,3,5]triazin-2-yl)-hydrazonomethyl]-
-2,6-dimethoxy-phenol (7)
[0254] This was synthesized from (6) using the method of Example
1a(iv). M/Z (LC-MS, ESP): Purity 97%, 395 [M+H].sup.+, R/T=4.08
mins.
Example 2
Synthesis of 6-(N'-Methylene-hydrazino)-pyrimidine-2,4-diamine
derivatives (12)
[0255] ##STR132## (i) Synthesis of 2,6-Dichloro-pyrimidin-4-ylamine
Derivatives (9)
[0256] To a cooled (-5.degree. C.) solution of
2,4,6-trichloro-pyrimidine (8)(2.73 mmol) in ethanol (6 ml) was
added the appropriate amine (2.73 mmol) and then Et.sub.3N (0.303
ml, 2.18 mmol) which was added in a dropwise fashion. The cooling
bath was removed and the reaction allowed to warm to room
temperature. Water was then added to the mixture which caused a
precipitate to form. The solid was removed by suction filtration
and washed with ice cold EtOH (6 ml) to give the desired product
which was then purified by flash chromatography (eluent typically
100% Hexanes going to 4:1--Hexanes:EtOAc) TABLE-US-00006 Yield m/z
RT Compound NRR' % [M + H].sup.+ (mins) 9a ##STR133## 85 235
4.02
(iia) Synthesis of 6-Chloro-pyrimidine-2,4-diamine Derivatives (10)
(where Amine Groups Different)
[0257] To a solution of the appropriate
2,6-dichloro-pyrimidin-4-ylamine derivative (9)(0.85 mmol) in
THF/EtOH (2:1, 1.5 ml) was added the appropriate amine (2.13 mmol)
in ethanol (1 ml). The mixture was stirred at room temperature
overnight and cooled to 0.degree. C. whereupon a precipitate
formed. The solid was removed by suction filtration, washed with
ice cold ethanol and dried in a vacuum desiccator to give the
desired product. TABLE-US-00007 Yield m/z RT NRR' NR''R''' % [M +
H].sup.+ (mins) 10a ##STR134## ##STR135## 85 283 5.09 10b
##STR136## ##STR137## 74 269 4.50 10c ##STR138## ##STR139## 100 385
5.01 10d ##STR140## ##STR141## 100 398 4.91
(iib) Synthesis of 6-Chloro-pyrimidine-2,4-diamine Derivatives (10)
(where Amine Groups Same)
[0258] Compound 10e was made by the method of Example 2(iia) using
double the amount of morpholine.
[0259] Compound 10f was made as follows: To a cooled (0.degree. C.)
solution of 2,4,6-trichloropyrimidine (8)(1.23 g, 6.7 mmol) in THF
(40 ml) under an inert atmosphere was added piperidine (3.32 ml,
33.6 mmol) which caused a white precipitate to form that made
stirring difficult. The mixture was heated to 50.degree. C. for 24
hrs whereupon it was cooled to room temperature and diluted with
water (40 ml). The organic extract was removed, dried using
MgSO.sub.4, filtered and concentrated in vacuo to give a colourless
solid. The crude residue was purified by flash chromatography
(SiO.sub.2) (70:30 going to 60:40--Hexanes:EtOAc as eluent) to give
the desired product (1.62 g, 86%) in analytically pure form.
TABLE-US-00008 Yield m/z RT NRR' NR''R''' % [M + H].sup.+ (mins)
10e ##STR142## ##STR143## 90 286 4.24 10f ##STR144## ##STR145## 97
281 5.69
(iii) Synthesis of 6-hydrazino-pyrimidine-2,4-diamine Derivatives
(11)
[0260] To suspension of the appropriate
6-Chloro-pyrimidine-2,4-diamine derivative (0.85 mmol) in 1-butanol
(1.0 ml) was added hydrazine hydrate (1.0 ml) The mixture was
heated to reflux and maintained at this temperature with stirring
for 48 hours. The mixture was cooled to room temperature and
concentrated in vacuo to typically give a red sticky residue. The
residue was triturated with EtOH to give a colourless solid.
TABLE-US-00009 Yield m/z RT NRR' NR''R''' R'''' % [M + H].sup.+
(mins) 11a ##STR146## ##STR147## H 99 282 2.88 11b ##STR148##
##STR149## H 80 279 3.32 11c ##STR150## ##STR151## H 74 295 3.16
11d ##STR152## ##STR153## H 99 380 3.47 11e ##STR154## ##STR155## H
80 394 3.47
(iv) Synthesis of 6-(N'-Methylene-hydrazino)-pyrimidine-2,4-diamine
derivatives (12)
[0261] These were synthesized from 11 using the method of Example
1a(iv). TABLE-US-00010 Purity m/z RT NRR' NR''R''' R'''' Ar % [M +
H].sup.+ (mins) 12a ##STR156## ##STR157## H ##STR158## 99 445 3.44
12b ##STR159## ##STR160## H ##STR161## 97 443 4.31 12c ##STR162##
##STR163## H ##STR164## 95 429 3.65 12d ##STR165## ##STR166## H
##STR167## 97 544 3.97 12e ##STR168## ##STR169## H ##STR170## 96
500 3.94 12f ##STR171## ##STR172## H ##STR173## 96 558 3.85 12g
##STR174## ##STR175## H ##STR176## 92 364 3.45 12h ##STR177##
##STR178## H ##STR179## 100 416 3.38 12i ##STR180## ##STR181## H
##STR182## 98 400 3.49
Example 3a
Synthesis of 2,6-dimethoxy-phenol-4-boronic acid (15)
[0262] ##STR183## (i) 4-Bromo-2,6-dimethoxy-phenol (14)
[0263] To a cooled (-78.degree. C.) solution of 2,6-dimetoxyphenol
(13)(15 g, 97.35 mmol) in CH.sub.2Cl.sub.2 (200 ml) was added
N-bromosuccinimide (17.4 g, 97.35 mmol) portionwise over twenty
minutes. The reaction mixture was stirred at -78.degree. C. under
an inert atmosphere for four hours before being allowed to warm to
room temperature where it was stirred for a further 16 hours. The
solvent was then removed in vacuo to give a slurry that was
purified by flash chromatography (SiO.sub.2)
(7:3--CH.sub.2Cl.sub.2:Hexanes) and then re-crystallised from
CH.sub.3Cl/hexanes to give the title compound as a white solid that
was analytically clean (9.66 g, 42.57%). m/z (LC-MS, ESP): 231
[M-H].sup.-, R/T=3.17 mins
(ii) 2,6-dimethoxy-phenol-4-boronic acid (15)
[0264] To a solution of 4-Bromo-2,6-dimethoxy-phenol (14)(9.32 g,
40 mmol) in anhydrous diethyl ether (100 ml) was added triisopropyl
borate (11 ml, 48 mmol). The reaction mixture was cooled to
-78.degree. C. and n-butyl lithium (1.7 M in pentane, 56 ml, 96
mmol) added under an inert atmosphere. The solution was stirred at
-78.degree. C. for a further 5 hours and then allowed to warm to
room temperature and maintained like this, with stirring, for a
further 16 hours. The reaction was then cooled to 0.degree. C. and
2M HCl carefully added until the pH was acidic. The mixture was
extracted using EtOAc (7.times.60 ml) and the organic extracts
combined, dried (MgSO.sub.4), filtered and concentrated in vacuo to
give a yellow slurry. The crude residue was purified by flash
chromatography (SiO.sub.2) (7:3--EtOAc:Hexanes) to give the title
compound (0.92 g, 11.62%) as a white solid. m/z (LC-MS, ESP): 197
[M-H].sup.-, R/T=0.52 mins.
Example 3b
Synthesis of
4-[1-(4,6-Di-morpholin-4-yl-[1,3,5]triazin-2-yl)-3H-imidazol-4-yl]-2,6-di-
methoxy-phenol (17a)
[0265] ##STR184## (i)
2-(4-Bromo-3H-imidazol-1-yl)-4,6-di-morpholin-4-yl-[1,3,5]triazine
(16)
[0266] To a cooled solution of 4-bromo-1H-imidazole (0.249 g, 2.0
mmol) in anhydrous dimethylformamide (4 ml) was slowly added sodium
hydride (60% dispersion in mineral oil) (0.088 g, 2.2 mmol). When
the evolution of gas has ceased (30 mins),
2-chloro-4,6-di-morpholin-4-yl-[1,3,5]triazine (3b)(0.571 g, 2.00
mmol) was added in a single portion and the resulting mixture
heated in a microwave reactor at 120.degree. C. for exactly 14
minutes (fixed temperature holdtime, high absorbtion setting). The
resulting brown/yellow slurry was diluted with water (10 ml) and
filtered. The filter cake was washed with cold water (2.times.10
ml) and then dried in a vacuum dessicator to give the title
compound in suitably pure form to be used without further
purification. m/z (LC-MS, ESP): 396 [M+H].sup.+, R/T=3.61 mins.
(ii)
4-[1-(4,6-Di-morpholin-4-yl-[1,3,5]triazin-2-yl)-3H-imidazol-4-yl]--
2,6-dimethoxy-phenol (17a)
[0267] To a microwave reaction vial containing a solution of
2-(4-Bromo-3H-imidazol-1-yl)-4,6-di-morpholin-4-yl-[1,3,5]triazine
(16)(0.317 g, 0.80 mmol) in anhydrous dioxane (3 ml) was added
tripotassium phosphate (0.34 g, 1.6 mmol) and
2,6-dimethoxy-phenol-4-boronic acid (15)(0.317 g, 1.6 mmol). The
mixture was degassed for 5 minutes by sonicating and bubbling
nitrogen through the solution before the addition of
bis(tri-butylphosphine)palladium(0) The vial was sealed and heated
while under the influence of microwave radiation at 170.degree. C.
for 11 minutes (fixed hold time). The crude reaction mixture was
then filtered and the filter cake washed with methanol (10 ml). The
solvent was removed in vacuo and the crude mixture submitted for
purification using preparative HPLC to give the desired product.
m/z (LC-MS, ESP): 470 [M-H].sup.-, R/T=3.23 mins.
[0268] (iii) The following two compounds were made in an analgous
fashion to compound 17a from compound 16: TABLE-US-00011 ##STR185##
Purity m/z RT Ar % [M + H].sup.+ (mins) 17b ##STR186## 98 433.0
3.23 17c ##STR187## 96 445.0 2.92
Example 3c
Synthesis of 4-[1-(4,6-Di-morpholin-4-yl-[1,3,5]
triazin-2-yl)-1H-pyrazol-4-yl]-2,6-dimethoxy-phenol (19)
[0269] ##STR188## (i)
2-(4-Bromo-pyrazol-1-yl)-4,6-di-morpholin-4-yl-[1,3,5]triazine
(18)
[0270] To a cooled (0.degree. C.) solution of 4-bromopyrazole (0.29
g, 2.0 mmol) in anhydrous DMF (4 ml) was added NaH (60% dispersion
in mineral oil, 0.088 g, 2.2 mmol) in a portionwise fashion over 10
minutes. The mixture allowed to warm to room temperature where it
was stirred for 30 minutes before the adition of
2-Chloro-4,6-di-morpholin-4-yl-[1,3,5]triazine (3b)(0.571 g, 2.00
mmol). The mixture was then heated under the influence of microwave
radiation (120.degree. C., 14 minutes). Upon cooling the reaction
was diluted with water (10 ml) and filtered. The filtercake was
washed with more cold water (10 ml), collected and dried to give
the title compound (92.4%, 0.73 g) in suitably pure form to be used
without any further purification. m/z (LC-MS, ESP): 396
[M+H].sup.+, R/T=3.56 mins.
(ii) 4-[1-(4,6-Di-morpholin-4-yl-[1,3,5]
triazin-2-yl)-1H-pyrazol-4-yl]-2,6-dimethoxy-phenol (19)
[0271] This was synthesized by the coupling of (15) and (18)
according to the method of Example 3b(ii). m/z (LC-MS, ESP): 470
[M-H].sup.-, R/T=3.23 mins.
Example 3d
Synthesis of
2,6-Dimethoxy-4-[1-(4-morpholin-4-yl-pyrimidin-2-yl)-1H-pyrazol-4-yl]-phe-
nol
[0272] ##STR189## (i) 4-(2-Chloro-pyrimidin-4-yl)-morpholine
(21)
[0273] To a cooled (0.degree. C.) suspension of
2,4-dichloropyrimidine (20)(1.0 g, 6.7 mmol) in ethanol (20 ml),
which was stirred under an inert atmosphere, was added
triethylamine (1.4 ml, 10.1 mmol) and then morpholine (0.59 ml, 6.7
mmol). The mixture was maintained at this temperature for 3 hours
whereupon it was concentrated in vacuo, diluted with NaOH (20 ml,
1M) and extracted with EtOAc (3.times.20 ml). The organic extracts
were combined, dried (Na.sub.2SO.sub.4), filtered and concentrated
in vacuo to give a colorless solid. The crude residue was
re-crystallised using EtOAc/Hexanes to give the title compound
(1.21 g, 90%) as a colourless solid which required no further
purification. m/z (LC-MS, ESP): 200 [M+H].sup.+, R/T=3.26 mins
(ii) 4-[2-(4-Bromo-pyrazol-1-yl)-pyrimidin-4-yl]-morpholine
(22)
[0274] To a cooled (0.degree. C.) solution of 4-bromo-1H-pyrazole
(0.74 g, 5.0 mmol) in anhydrous DMF (7 ml) was added NaH (60%
dispersion in mineral oil, 0.22 g, 5.5 mmol) in a portionwise
fashion over 10 minutes. The mixture was stirred like this for 30
minutes before the addition of
4-(2-chloro-pyrimidin-4-yl)-morpholine (21)(1.0 g, 5.00 mmol). The
reaction was then heated under the influence of microwave radiation
(120.degree. C., 14 minutes, fixed hold time, high absorption
setting). The reaction was then cooled to room temperature and
water added (14 ml) which caused a precipitate to form. The solid
was collected by filtration, washed with water and dried in a
desiccator to give the title compound (1.44 g, 93%) in sufficiently
pure form to be used without any further purification. m/z (LC-MS,
ESP): 310 [M+H].sup.+, R/T=3.08 mins.
(iii)
2,6-Dimethoxy-4-[1-(4-morpholin-4-yl-pyrimidin-2-yl)-1H-pyrazol-4--
yl]-phenol (23)
[0275] This was synthesized by the coupling of (15) and (18)
according to the method of Example 3b(ii) to give a crude residue
which was submitted for purification by preparative HPLC to give
the desired product m/z (LC-MS, ESP): 470.4 [M+H].sup.+, R/T=3.23
mins.
Example 3e
Synthesis of
2,6-Dimethoxy4-[2-(2-morpholin-4-yl-pyrimidin4-yl)-thiazol-4-yl]-phenol
(27)
[0276] ##STR190## (i) 4-(4-Bromo-thiazol-2-yl)-2-chloro-pyrimidine
(25)
[0277] To a cooled (-78.degree. C.) solution of 2,4-dibromothiazole
(24)(0.73 g, 3.0 mmol) in anhydrous diethylether (7 ml) was added
n-butyllithium (2.5M in hexane, 1.5 ml, 3.28 mmol) in a dropwise
fashion via syringe. The yellow solution was stirred at -78.degree.
C. for 15 minutes before the addition of a suspension of
2-chloropyrimidine (20)(2.73 mmol, 0.313 g) in anhydrous
diethylether (8 ml). The mixture was allowed to warm to room
temperature and maintained like this, with stirring for 16 hours.
The mixture was quenched carefully by dropwise addition of water
(0.061 ml, 3.41 mmol) in THF (0.7 ml) and then DDQ (0.681 g, 3.0
mmol) added to effect aromatization. The mixture was cooled to 020
C. and 3M NaOH .sub.(aq) (2.28 ml, 6.83 mmol) added which caused a
sticky solid to adhere to bottom of the reaction vessel. The
solvents were collected, dried (MgSO.sub.4), filtered and
concentrated in vacuo to give the title compound (0.58 g, 69.8%) in
suitably clean form to be used without further purification. m/z
(LC-MS, ESP): 327 [M+H].sup.+, R/T=3.73 mins.
(ii) 4-[4-(4-Bromo-thiazol-2-yl)-pyrimidin-2-yl]-morpholine
(26)
[0278] To a solution of
4-(4-Bromo-thiazol-2-yl)-2-chloro-pyrimidine (25)(0.498 g, 1.8
mmol) in EtOH (8 ml) was added powdered potassium carbonate (0.274
g, 1.98 mmol) and morpholine (0.17 ml, 1.98 mmol). The mixture was
heated under the influence of microwave radiation (10 minutes,
90.degree. C., high absorption setting). The reaction mixture was
then allowed to cool to room temperature and filtered through a
thin pad of silica before being concentrated in vacuo. The crude
residue was purified by flash chromatography (SiO.sub.2) using
Hexanes:EtOAc--(9:1) as eluent to give the title compound (0.18 g,
30.5%) in analytically pure form. m/z (LC-MS, ESP): 327
[M+H].sup.+, R/T=3.92 mins.
(iii)
2,6-Dimethoxy-4-[2-(2-morpholin-4-yl-pyrimidin-4-yl)-thiazol-4-yl]-
-phenol (27)
[0279] This was synthesized by the coupling of (15) and (26)
according to the method of Example 3b(ii) to give a crude residue
which was submitted for purification by flash chromatography
(SiO.sub.2) (eluent--9:1--MeOH:CH.sub.2Cl.sub.2) to give an orange
solid (30.0%) in analytically pure form. m/z (LC-MS, ESP): 401.3
[M+H].sup.+, R/T=3.66
Example 3f
Synthesis of
2,6-Dimethoxy4-[1-(4-morpholin-4-yl-pyrimidin-2-yl)-1H-imidazol-4-yl]-phe-
nol (29)
[0280] ##STR191## (i)
4-[2-(4-Bromo-imidazol-1-yl)-pyrimidin-4-yl]-morpholine (28)
[0281] To a cooled (0.degree. C.) solution of 4-bromo-1-H-imidazole
(0.8 g, 4.0 mmol) in anhydrous DMF (5.0 mmol) was added NaH (60%
dispersion in mineral oil, 0.176 g, 4.4 mmol) in a portionwise
fashion over 10 minutes. When gas evolution had ceased,
4-(2-Chloro-pyrimidin-4-yl)-morpholine (21)(0.79 g, 4.00 mmol) was
added and the mixture heated under the influence of microwave
radiation (120.degree. C., 14 min, fixed hold time, pre-stirring 10
seconds, high absorption setting). Water (14 ml) was added to the
reaction mixture which caused a precipitate to form. The
precipitate was removed by filtration, washed with water (10 ml)
and dried in a desiccator to give the title compound (1.17 g,
94.4%) in suitably clean form to be used without any further
purification. m/z (LC-MS, ESP): 310 [M+H].sup.+, R/T=3.79 mins
(ii)
2,6-Dimethoxy-4-[1-(4-morpholin-4-yl-pyrimidin-2-yl)-1H-imidazol-4--
yl]-phenol (29)
[0282] This was synthesized by the coupling of (15) and (28)
according to the method of Example 3b(ii) to give a crude residue
that was purified by preparative HPLC to give the title compound
m/z (LC-MS, ESP): 384.4 [M+H].sup.+, R/T=2.80 mins.
Example 4
Synthesis of N-Methylene-N'-pyrido[3,4-d]pyramid in-4-yl-hydrazine
Derivatives
[0283] ##STR192## (i) Pyrrolo[3,4-c]pyridine-1,3-dione (31)
[0284] A suspension of cinchomeronic acid (30)(50 g, 300 mmol) in
acetic anhydride (123.5 g, 1200 mmol) was heated to reflux
(140-150.degree. C.) until all solid material dissolved and the
mixture was homogeneous. The mixture was then cooled and
concentrated in vacuo. Acetamide (50 g, 846 mmol) was then added
and the mixture heated to 140.degree. C. for 3 hours whereupon it
was then cooled to room temperature. The solid residue that formed
upon cooling was pulverized and triturated with water (100 ml),
filtered and washed with more water and dried in a desiccator to
give the title compound (42.26 g, 95.1%) in suitably pure form to
be used without any further purification. m/z (LC-MS, ESP): 149
[M+H].sup.+, R/T=0.44 mins.
(ii) 3-Amino-isonicotinic acid (32)
[0285] NaOH (10% aqueous, 640 ml) was cooled to 7.degree. C. and
bromine (15 ml, 286.82 mmol) added dropwise.
Pyrrolo[3,4-c]pyridine-1,3-dione (41.711 g, 281.6 mmol) was then
added to the reaction mixture before it was heated to 80.degree. C.
for 30 minutes. After this time the reaction was allowed to warm to
37.degree. C. and the pH modified to 5.5 by the addition of acetic
acid (70 ml). A suspension formed that was removed by filtration
and washed with 20 ml of ice cold methanol to give the title
compound (26.58 g, 68.33%) in a suitably clean form to be used
without any further purification. m/z (LC-MS, ESP): 139
[M+H].sup.+, R/T=0.72 mins.
(iii) Pyrido[3,4-d]pyrimidin-4-ol (33)
[0286] A mixture of 3-amino-isonicotinic acid (32)(26.24 g, 190.0
mmol) and formamidine acetate (39.56 g, 380 mmol) in
dimethylacetamide (100 ml) was stirred and heated to 150.degree. C.
The reaction was maintained at this temperature with stirring for
12 hours before it was allowed to cool to 25.degree. C. and then
basified with sodium bicarbonate solution (5% aqueous) until pH 7-8
was attained. The resultant pale brown solid was removed by
filtration, washed with water (20 ml) and dried in a desiccator to
give the desired compound (24.50 g, 87.63%) which required no
further purification. m/z (LC-MS, ESP): 148 [M+H].sup.+, R/T=1.09
mins.
(iv) 4-Chloro-pyrido[3,4-d]pyrimidine (34)
[0287] A suspension of pyrido[3,4-d]pyrimidin-4-ol (33)(1.47 g, 10
mmol) in thionylchloride (30 ml) and dimethylformamide (50 .mu.l,
cat.) was heated to reflx (90.degree. C.) for 1 hour. The mixture
was then cooled and concentrated in vacuo and then diluted with
CH.sub.2Cl.sub.2 (50 ml) which caused a suspension to form. The
solid was removed by filtration, washed with cold CH.sub.2Cl.sub.2
(10 ml) to give the title compound (1.65 g, 99.4%) in sufficiently
pure form to be used without any further purification. m/z (LC-MS,
ESP): 166 [M+H].sup.+, R/T=2.82 mins.
(v) Pyrido[3,4-d]pyrimidin-4-yl-hydrazine (35)
[0288] To a suspension of 4-Chloro-pyrido[3,4-d]pyrimidine
(34)(1.65 g, 10 mmol) in anhydrous THF (10 ml) was added hydrazine
(1M in THF, 30 ml, 30 mmol). The reaction mixture was stirred at
room temperature for 5 hours whereupon a yellow precipitate formed.
The solid was removed by filtration, washed with cold THF (10 ml)
and dried to give the title compound (1.56 g, 96.9%) as the sole
product which required no further purification. m/z (LC-MS, ESP):
162 [M+H].sup.+, R/T=0.85 mins.
(vi) N-Methylene-N'-pyrido[3,4-d]pyramid in-4-yl-hydrazine
Derivatives (36)
[0289] These were synthesized from 35 using the method of Example
1a(iv). TABLE-US-00012 Purity m/z RT Compound Ar % [M + H].sup.+
(mins) 36a ##STR193## 96 298 3.35 36b ##STR194## 97 282 3.31 36c
##STR195## 92 282 3.56 36d ##STR196## 94 326 3.48
Example 5
Synthesis N-(6,7-Dimethoxy-quinazolin-4-yl)-N'-methylene-hydrazine
Derivatives
[0290] ##STR197## (i) 6,7-Dimethoxy-quinazolin-4-ol (38)
[0291] 2-amino-4,5-dimethylbenzoic acid (37)(5 g, 25.30 mmol) and
formamidine acetate (5.2 g, 50.00 mmol) were dissolved in
2-methoxyethanol (80 ml) and the mixture heated to reflux for 16
hours. The mixture was cooled and concentrated in vacuo and
suspended in a small volume of water. Sodium bicarbonate (5%
aqueous solution) was added carefully (gas evolution) until pH 7
was attained. The suspension was filtered and the filtercake washed
with water to give the title compound (4.50 g, 86.2%) as a brown
powder which required no further purification. m/z (LC-MS, ESP):
207 [M+H].sup.+, R/T=3.16 mins
(ii) 4-Chloro-6,7-dimethoxy-quinazoline (39)
[0292] To a suspension of 6,7-Dimethoxy-quinazolin-4-ol (1.65 g,
8.0 mmol) and phosporousoxychloride (1.52 ml, 16.4 mmol) in
1,2-dichloroethane (16 ml) was added diisopropylamine (3.48 ml, 20
mmol) in a dropwise fashion. The mixture was then heated to
80.degree. C. under an inert atmosphere for 16 hours. After this
time the reaction was cooled to room temperature and concentrated
in vacuo to dryness, dissolved in CH.sub.2Cl.sub.2 (50 ml) and
washed with sodium bicarbonate solution (5% aqueous, 2*25 ml). The
organic layer was separated, dried using MgSO.sub.4, filtered and
concentrated in vacuo to give a brown residue that was purified by
flash chromatography (SiO.sub.2) eluted with
CH.sub.2Cl.sub.2:EtOAc--2:98 then 5:95 to give the title compound
(1.6 g, 88.9%) as a yellow solid. m/z (LC-MS, ESP): 207
[M+H].sup.+, R/T=3.51 mins
(iii) (6,7-Dimethoxy-quinazolin-4-yl)-hydrazine (40)
[0293] To a suspension of 4-Chloro-6,7-dimethoxy-quinazoline (0.20
g, 0.89 mmol) in anhydrous THF (0.5 ml) was added hydrazine (1M in
THF, 2.0 ml, 2.0 mmol). The mixture was stirred at room temperature
for 16 hours whereupon a precipitate had formed which was removed
by filtration and washed with cold THF to give the desired product
(177 mg, 91%) as a sticky off white solid which was sufficiently
pure to be used without any further purification. m/z (LC-MS, ESP):
221 [M+H].sup.+, R/T=2.48 mins.
(iv) N-(6,7-Dimethoxy-quinazolin-4-yl)-N-methylene-hydrazine
derivatives (41)
[0294] These were synthesised from 40 using the method of Example
1a(iv). TABLE-US-00013 Purity m/z RT Compound Ar % [M + H].sup.+
(mins) 41a ##STR198## 100 341 3.28
Example 6
Synthesis of 4-[(3-morpholin-4-yl-phenyl)-hydrazonomethyl]-phenol
derivatives
[0295] ##STR199## (i) 4-(3-Nitro-phenyl)-morpholine (43)
[0296] To a solution of 3-nitroaniline (42)(5.52 g, 40.00 mmol) in
anhydrous dimethylacetamide (15 ml) was added 2-bromoethylether
(7.52 ml, 60.00 mmol) and N,N-diisopropylethylamine (13.94 ml, 80.0
mmol). The mixture was then heated to 120.degree. C. for 6 hours.
After this time the reaction was cooled to room temperature which
saw the mixture take the form of a slurry. The slurry was dissolved
in CH.sub.2Cl.sub.2 (80 ml) and washed with 0.2 M HCl (3.times.30
ml). The organic layer was separated, dried (MgSO.sub.4), filtered
and concentrated in vacuo to give a brown semi-solid residue that
was triturated with Et.sub.2O to give the desired product (8.33 g,
79.7%) in suitably clean form to be used without any further
purification. m/z (LC-MS, ESP): 209 [M+H].sup.+, R/T=3.46 mins
(ii) 3-Morpholin-4-yl-phenylamine (44)
[0297] To a cooled (0.degree. C.) solution of
4-(3-nitro-phenyl)-morpholine (43)(4.16 g, 20 mmol) in methanol (50
ml) was added Pd/C (10% loading, 460 mg). The mixture was stirred
at room temperature under an H.sub.2 (1 atm) for 16 hrs. The
mixture was then filtered through a Celite.TM. pad, the filtrate
dried using MgSO.sub.4, filtered and concentrated in vacuo to give
the title compound (3.39 g, 95.2%) as an orange solid that was
suitably clean to be used without any further purification. m/z
(LC-MS, ESP): 179 [M+H].sup.+, R/T=1.69 mins.
(iii) (3-Morpholin-4-yl-phenyl)-hydrazine (45)
[0298] To a cooled (-5 .degree. C.) solution of
3-morpholin-4-yl-phenylamine (44)(0.18 g, 1.00 mmol) in 2M
HCl.sub.(aq) was added sodium nitrite (69 mg, 1.00 mmol in 1 ml
water) dropwise. The red solution was stirred at -5.degree. C. for
10 minutes before the addition of tin (II) chloride dihydrate (1.13
g, 5.0 mmol). The mixture was stirred vigorously and allowed to
warm to room temperature over the period of 1 hour. 2M
NaOH.sub.(aq) was added until the solution was basic (pH=8), then
extracted with EtOAc (2.times.20 ml). The combined organic extracts
were dried using MgSO.sub.4, filtered and concentrated in vacuo to
give the desired product (0.15 g, 79.0%)
(3-Morpholin-4-yl-phenyl)-hydrazine. m/z (LC-MS, ESP): 194.4
[M+H].sup.+, R/T=1.00 mins.
(iv) 4-[(3-morpholin-4-yl-phenyl)-hydrazonomethyl]-phenol
derivatives (46)
[0299] These were synthesized from 45 using the method of Example
1a(iv). TABLE-US-00014 Purity m/z RT Compound Ar % [M + H].sup.+
(mins) 46a ##STR200## 90 330 2.81 46b ##STR201## 90 358 3.27
Example 7
Synthesis of
5-[(4,6-Di-morpholin-4-yl-[1,3,5]triazin-2-yl)-hydrazonomethyl]
derivatives (47)
[0300] ##STR202##
[0301] To a mixture of
(4,6-Di-morpholin-4-yl-[1,3,5]triazin-2-yl)-hydrazine (4a)(0.02 g,
0.070 mmol) and the appropriate aromatic acid (47)(0.012 g, 0.070
mmol) in anhydrous DMA (0.5 ml) was added diisopropylethylamine (15
.mu.l, 0.085 mmol) and then
O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate (0.03 g, 0.08 mmol). The mixture was stirred at
room temperature for 16 hours whereupon it was submitted for
purification by preparative HPLC to give the desired product.
TABLE-US-00015 Purity m/z RT Compound Ar % [M + H].sup.+ (mins) 47a
##STR203## 100 434 2.44 47b ##STR204## 90 462 2.68
Example 8
Synthesis of
2,6-Dimethoxy-4-[3-(2-morpholin-4-yl-pyrimidin-4-yl)-3H-imidazol-4-yl]-ph-
enol (50)
[0302] ##STR205## (i) 4-(5-Bromo-imidazol-1-yl)-2-chloro-pyrimidine
(48)
[0303] To a solution of 2,4-dichloropyrimidine (0.447 g, 3 mmol) in
anhydrous DMF (4 ml) was added potassium carbonate (0.415 g, 3
mmol). The reaction mixture was cooled (0.degree. C.) under an
inert atmosphere before the addition of 5-bromo-1-H-imidazole
(0.441 g, 3 mmol) as solution in DMF (2 ml). The reaction was then
allowed to stir at this temperature for a further 3 hours whereupon
water (3 ml) was added. The resultant white precipitate was removed
from the mixture by filtration and washed with water before being
dried to give the title compound as a white solid (0.18 g, 23%)
which was suitably pure to be used without further purification.
m/z (LC-MSW, ESP):259.2,261.2 (bromine isotopes) [M+H].sup.+,
R/T=3.47 mins.
(ii) 4-[4-(5-Bromo-imidazol-1-yl)-pyrimidin-2-yl]-morpholine
(49)
[0304] To a cooled (0.degree. C.) solution of morpholine (0.256 g,
2.94 mmol) in anhydrouse DMF (5 ml) was added NaH (0.117 g, 2.94
mmol, 60% disp' in mineral oil). The mixture was stirred at this
temperature for 30 minutes before the addition of
4-(4-Bromo-imidazol-1-yl)-2-chloro-pyrimidine (0.64 g, 2.45 mmol).
The reaction vessel was sealed and heated under the infuenceof
microwave radiation for 7 minutes (120.degree. C., High absorption
setting). Upon cooling the mixture was diluted with water (7 ml)
and the resultant yellow precipitate removed by filtration and
purified by flash chromatography (SiO.sub.2) (4:1--Hexanes:EtOAc)
to give the title compound as a white solid in analytically (0.76
g, 38.6%) pure form. m/z (LC-MSW, ESP):310.2 [M+H].sup.+, R/T=3.21
mins.
(iii)
2,6-Dimethoxy-4-[3-(2-morpholin-4-yl-pyrimidin-4-yl)-3H-imidazol-4-
-yl]-phenol (50)
[0305] To a solution of
4-[4-(4-Bromo-imidazol-1-yl)-pyrimidin-2-yl]-morpholine (0.20 g,
0.65 mmol) in anhydrous dioxane (6 ml) and anhydrous DMA (0.6 m)
was added tripotassium phosphate (0.28 g, 1.3 mmol) and
2,6-dimethoxy-phenol-boronic acid (0.18 g, 0.91 mmol). The
resultant mixture was degassed with sonication for 10 minutes
before the addition of bis(tri-butylphospine)palladium (0.017 g,
0.033 mmol) and degassing for a further 5 minutes. The reaction
vessel was sealed and heated under the influence of microwave
radiation (170.degree. C., 11 min, low absorption setting). Upon
completion, the reaction was filtered through a thin silica plug
which was then washed with 10% methanol/CH.sub.2Cl.sub.2. The
filtrate was concentrated in vacuo and the crude residue purified
by flash chromatography (SiO.sub.2) (1:1--EtOAc:Hexanes) to give
the desired product (0.24 g, 96%) as a white crystalline solid in
analytically pure form. m/z (LC-MSW, ESP):384.4 [M+H].sup.+,
R/T=2.90 mins.
Example 9
Synthesis of
2,6-Dimethoxy-4-[1-(2-morpholin-4-yl-pyrimidin4-yl)-1H-imidazol-4-yl]-phe-
nol (53)
[0306] ##STR206## (i) 4-(4-Bromo-imidazol-1-yl)-2-chloro-pyrimidine
(51)
[0307] To a solution of 2,4-dichloropyrimidine (0.447 g, 3 mmol) in
anhydrous DMF (4 ml) was added potassium carbonate (0.415 g, 3
mmol). The reaction mixture was cooled (0.degree. C.) under an
inert atmosphere before the addition of 4-bromo-1-H-imidazole
(0.441 g, 3 mmol) as solution in DMF (2 ml). The reaction was then
allowed to stir at this temperature for a further 3 hours whereupon
water (3 ml) was added. The resultant white precipitate was removed
from the mixture by filtration and washed with water before being
dried to give the title compound as a white solid (0.18 g, 23%)
which was suitably pure to be used without further purification.
m/z (LC-MSW, ESP):259.2,261.2 (bromine isotopes) [M+H].sup.+,
R/T=3.47 mins.
(ii) 4-[4-(4-Bromo-imidazol-1-yl)-pyrimidin-2-yl]-morpholine
(52)
[0308] To a cooled (0.degree. C.) solution of morpholine (0.256 g,
2.94 mmol) in anhydrouse DMF (5 ml) was added NaH (0.117 g, 2.94
mmol, 60% disp' in mineral oil). The mixture was stirred at this
temperature for 30 minutes before the addition of
4-(4-Bromo-imidazol-1-yl)-2-chloro-pyrimidine (0.64 g, 2.45 mmol).
The reaction vessel was sealed and heated under the infuenceof
microwave radiation for 7 minutes (120.degree. C., High absorption
setting). Upon cooling the mixture was diluted with water (7 ml)
and the resultant yellow precipitate removed by filtration and
purified by flash chromatography (SiO.sub.2) (4:1--Hexanes:EtOAc)
to give the title compound as a white solid in analytically (0.76
g, 38.6%) pure form. m/z (LC-MSW, ESP):310.3 [M+H].sup.+, R/T=3.26
mins.
(iii)
2,6-Dimethoxy-4-[3-(2-morpholin-4-yl-pyrimidin-4-yl)-3H-imidazol-4-
-yl]-phenol (53)
[0309] To a solution of
4-[4-(4-Bromo-imidazol-1-yl)-pyrimidin-2-yl]-morpholine (0.20 g,
0.65 mmol) in anhydrous dioxane (6 ml) and anhydrous DMA (0.6 m)
was added tripotassium phosphate (0.28 g, 1.3 mmol) and
2,6-dimethoxy-phenol-boronic acid (0.18 g, 0.91 mmol). The
resultant mixture was degassed with sonication for 10 minutes
before the addition of bis(tri-butylphospine)palladium (0.017 g,
0.033 mmol) and degassing for a further 5 minutes. The reaction
vessel was sealed and heated under the influence of microwave
radiation (170.degree. C., 11 min, low absorption setting). Upon
completion, the reaction was filtered through a thin silica plug
which was then washed with 10% methanol/CH.sub.2Cl.sub.2. The
filtrate was concentrated in vacuo and the crude residue purified
by flash chromatography (SiO.sub.2) (1:1--EtOAc:Hexanes) to give
the desired product (0.24 g, 96%) as a white crystalline solid in
analytically pure form. m/z (LC-MSW, ESP):384.4 [M+H].sup.+,
R/T=2.72 mins.
Example 10
Synthesis of 2-[N'-Ethylidene-hydrazino]-pyrimidin-4-ylamine
derivatives (56)
[0310] ##STR207## (i) 2-Chloro-pyrimidin-4-ylamine derivatives
(54)
[0311] To a cooled (0.degree. C.) suspension of
2,4-dichloropyrimidine (10 g, 67.6 mmol) and potassium carbonate
(9.3 g, 67.6 mmol) in anhydrous DMA (45 ml) was added the
appropriate amine (1 equiv, 67.6 mmol) in a dropwise fashion over
30 minutes. The mixture was then maintained at this temperature for
a further 3 hours whereupon it was poured carefully onto crushed
ice. The resultant white precipitate was removed by filtration and
washed with water to give the desired adduct.
[0312] 54a: NRR'=morpholino: m/z (LC-MSW, ESP):200.4 [M+H].sup.+,
R/T=3.98 mins.
(ii) 2-Hydrazino-pyrimidin-4-ylamine derivatives (55)
[0313] To a solution of the appropriate
2-Chloro-pyrimidin-4-ylamine derivative (1 equiv, 46.1 mmol) in
ethanol (45 ml) was added hydrazine hydrate (7.2 ml, 231 mmol). The
mixture was heated to 90.degree. C. under an inert atmosphere for 4
hours. The reaction was then cooled to 0.degree. C. and the
resultant precipitate collected by filtration. The collected
product was washed with cold water and recrystallised from the
minimum quantity of hot ethanol to give the desired product in
suitably clean form to be used without further purification.
[0314] 55a: NRR'=morpholino: m/z (LC-MSW, ESP):195.4 [M+H].sup.+,
R/T=0.37 mins.
(iii) 2-[N'-arylylidene-hydrazino]-pyrimidin-4-ylamine derivatives
(56)
[0315] To a solution of the appropriate of
2-Hydrazino-pyrimidin-4-ylamine derivative (1 equiv, 0.26 mmol) in
ethanol was added p-toluenesulfonic acid (0.05 equiv, 0.013 mmol)
and the appropriate aldehyde (1.2 equiv, 0.30 mmol). The reaction
vessel was sealed and heated under the influence of microwave
radiation (10 minutes, 130.degree. C., high absorption setting).
The reaction was cooled and filtered. The filtrant was washed with
cold ethanol to give a white solid which corresponded to the
desired product. TABLE-US-00016 Purity m/z RT Compound NRR' Ar % [M
+ H].sup.+ (mins) 56a ##STR208## ##STR209## 360.3 2.49 56b
##STR210## ##STR211## 323.3 2.62
Example 11
Synthesis of 4-(4-aryl-thiazol-2-yl)-pyrimidin-2-ylamine
derivatives (59)
[0316] ##STR212## (i) 4-(4-Bromo-thiazol-2-yl)-2-chloro-pyrimidine
(57)
[0317] To a cooled (-78.degree. C.) solution of 2,4-dibromothiazole
(1.22 g, 5.0 mmol) in anhydrous diethyl ether (15 ml) was added
n-Butyllithium (2.2 ml of 2.5 M solution in Hexanes, 5.5 mmol) in a
dropwise fashion. The mixture was maintained at this temperature,
with stirring, for 1 hour before a suspension of 2-chloropyrimidine
(0.85 g, 7.5 mmol) in anhydrous diethylether (15 ml) was added
slowly and the resulting solution allowed to slowly warm up to room
temperature. The misture was then allowed to stir at room
temperature for 1 hr before being quenched with water (0.113 ml,
5.0 mmol) in THF (1.25 ml) and treated with DDQ (1.25 g, 5.4 mmol)
in THF (6.25 ml). The mixture was then stirred at 25.degree. C. for
15 minutes, cooled to 0.degree. C., treated with hexanes (4.16 ml)
then cold 2M NaOH (6.25 ml, 12.5 mmol). The organic extract was
removed and remaing aqueous fraction extracted further with
CH.sub.2Cl.sub.2 (3.times.20 ml). The organic extracts were
combined, dried (MgSO.sub.4), filtered and concentrated in vacuo to
give a sticky brown residue which was purified by flash
chromatography (SiO.sub.2) (1:1--CH.sub.2Cl.sub.2:Hexanes going to
7:3--CH.sub.2Cl.sub.2:Hexanes) to give a white solid (1.38 g,
47.1%) corresponding to the title compound in analytically pure
form. m/z (LC-MSW, ESP):278.0 [M+H].sup.+, R/T=3.90 mins
(ii) 2-Chloro-4-(4-aryl-thiazol-2-yl)-pyrimidine derivatives
(58)
[0318] To a solution of Synthesis of
4-(4-Bromo-thiazol-2-yl)-2-chloro-pyrimidine (0.2 g, 1 eq) in
anhydrous dioxane (8 ml) was added the appropriate boronic acid or
ester (3.2 eq) and tripotassium phosphate (4 equiv). The mixture
was degassed with sonication for 10 minutes before
bis(tri-butylphosphine)palladium (0.05 equiv) was added. The
resulting solution was degassed with sonication for a further 10
minutes. The reaction vessel was then sealed and heated under the
influence of microwave radiation (130.degree. C., 1 hour, medium
absorption setting). Upon cooling, the reaction mixture was
concentrated in vacuo to give a sticky oil which was then purified
by flash chromatography (SiO.sub.2) (7:3--CH.sub.2Cl.sub.2:Hexanes
going to 99:1--CH.sub.2Cl.sub.2:MeOH) to give the desired compound
in analytically pure form.
(iii) 4-(4-aryl-thiazol-2-yl)-pyrimidin-2-ylamine derivatives
(59)
[0319] To a solution of the appropriate chloropyrimidine derivative
(1 equiv, 0.14 mmol) in ethanol (2 ml) was added potassium
carbonate (2.1 equiv) and the appropriate amine (1.1 equiv). The
reaction vessel was sealed and heated under the influence of
microwave radiation (90.degree. C., 10 minutes, high absorption
setting). The crude reaction was then filtered through a thin
silica pad before being purified by preparative HPLC to give the
desired products. TABLE-US-00017 Purity m/z RT Compound NRR' Ar %
[M + H].sup.+ (mins) 59a ##STR213## ##STR214## 99 377.2 3.94 59b
##STR215## ##STR216## 99 415.3 3.33 59c ##STR217## ##STR218## 99
415.3 3.45 59d ##STR219## ##STR220## 99 429.0 4.85 59e ##STR221##
##STR222## 99 401.0 3.68 59f ##STR223## ##STR224## 99 415.0 4.43
59g ##STR225## ##STR226## 99 355 4.39 59h ##STR227## ##STR228## 89
445 3.43 59i ##STR229## ##STR230## 95 415.0 4.72 59j ##STR231##
##STR232## 99 429 4.86
Example 12
Synthesis of 4-(5-aryl-furan-2-yl)-pyrimidin-2-ylamine derivatives
(62)
[0320] ##STR233## (i) 4-(5-Bromo-furan-2-yl)-2-chloro-pyrimidine
(60)
[0321] To a cooled (-78.degree. C.) solution of 2,5-dibromofurane
(3.06 g, 8.88 mmol) in anhydrous diethyl ether (50 ml) was added
n-Butyllithium (3.9 ml of 2.5M solution in Hexanes, 9.77 mmol). The
mixture was stirred at this temperature for 90 minutes before the
addition of 2-chloropyrimidine. The mixture was stirred for a
further 30 minutes before being warmed to room temperature and
stirred for further 2 hours. DDQ (2 g, 8.88 mmol) was them added to
the solution which was stirred for 30 minutes before being
concentrated in vacuo to give a thick brown syrup. The syrup was
dissolved in EtOAc and washed with saturated sodium carbonated
solution. The organic extract was removed, dried (MgSO.sub.4),
filtered and concentrated in vacuo to give a crude residue which
was purified by flash chromatography (SiO.sub.2) (100% hexane going
to 7:2--hexane:EtOAc) to give the title compound (3.06 g, 40.20%)
in pure form. m/z (LC-MSW, ESP):346 [M+H].sup.+, R/T=4.41 mins
(ii) 4-(5-Bromo-furan-2-yl)-pyrimidin-2-ylamine derivatives
(61)
[0322] To a solution of 4-(5-Bromo-furan-2-yl)-2-chloro-pyrimidine
(1.23 g, 4.74 mmol) in ethanol (60 ml) was added the appropriate
amine (2.5 equiv). The mixture was heated to 70.degree. C. for 10
hrs before being cooled, and concentrated in vacuo to give a
slurry. The residue was dissolved in EtOAc (100 ml) and washed with
water (100 ml). The organic extract was separated, and dried
(MgSO.sub.4) before being filtered and concentrated in vacuo to
give the desired product in suitably clean form to be used without
further purification.
[0323] 61a: NRR'=morpholino: m/z (LC-MSW, ESP):310 [M+H].sup.+,
R/T=3.33 mins
(iii) 4-(5-aryl-furan-2-yl)-pyrimidin-2-ylamine derivatives
(62)
[0324] To a solution of the appropriate
4-(5-Bromo-furan-2-yl)-pyrimidin-2-ylamine derivative (1 equiv,
0.081 mmol) in anhydrous dioxane modified with 10% DMF (1.5 ml
total) was added tripotassium phosphate (2 eq). The solution was
degassed with sonication for 10 minutes prior to the addition of
bis(tri-butylphosphine)palladium (0.06 equivs) and degassing, with
sonication, for a further 5 minutes. The reaction vessel was then
sealed and heated under the influence of microwave radiation (26
minutess, 170.degree. C., medium absorption setting). The mixture
was cooled, and filtered through a silica plug, concentrated in
vacuo and purified by preparative HPLC to give the desired
products. TABLE-US-00018 Purity m/z RT Compound NRR' Ar % [M +
H].sup.+ (mins) 62a ##STR234## ##STR235## 87 400 4.31
Example 13
Synthesis of 4-(5-aryl-furan-2-yl)-2,6-dimorpholino-pyrimidine
derivatives (66)
[0325] ##STR236## (i) 2,4-Dichloro-6-furan-2-yl-pyrimidine (63)
[0326] To a solution of 2,4,6-trichloropyrimidine (0.5 g, 2.73
mmol), 2-furanboronic acid (0.152 g, 1.36 mmol), potassium
carbonate (0.377 g, 1.36 mmol)) in toluene (2.5 ml) was added
tetrakis(triphenylphosphine)palladium (0.08 g, 0.068 mmol). The
reaction vessel was sealed and heated under the influence of
microwave radiation (130.degree. C., 600 seconds, low absorption
setting). The crude reaction was concentrated in vauo to give an
orange oil which was purified by flash chromatography (SiO.sub.2)
(19:1--Hexanes:EtOAc) to give the title compound (342 mg, 58%) in
suitably clean form to be used without further purification. m/z
(LC-MSW, ESP):215.1 [M+H].sup.+, R/T=4.68 mins
(ii) 4-(5-Bromo-furan-2-yl)-2,6-dichloro-pyrimidine (64)
[0327] To a stirred solution of
2,4-Dichloro-6-furan-2-yl-pyrimidine (1.44 g, 6.71 mmol) in DMF (20
ml) was added N-bromosuccinimide (1.31 g, 7.38 mmol) in a
portionwise fashion. The resultant mixture was stirred at room
temperature for a 2.5 hours before being diluted in EtOAc (50 ml)
and washed with water (2.times.50 ml). The organic extract was
dried (MgSO.sub.4), filtered and concentrated in vacuo to give an
orange, semi-crystalline slurry. The crude residue was washed with
ether and filtered to leave the desired product (1.29 g, 99%) as a
whited crystalline solid in suitably clean form to be used without
any further purification. m/z (LC-MSW, ESP):294 [M+H].sup.+,
R/T=5.09 mins.
(iii) 4-(5-bromo-furan-2-yl)-2,6-dimorpholino-pyrimidine (65)
[0328] To a solution of
4-(5-Bromo-furan-2-yl)-2,6-dichloro-pyrimidine (1.93 g, 6.51 mmol)
in DMA (35 ml) was added morpholine (2.83 g, 32.54 mmol) and
N,N-diisopropylethylamine (4.21 g, 32.54 mmol). The reaction
mixture was heated to 70.degree. C. for 7 hours whereupon it was
cooled and diluted with EtOAc (100 ml) and then washed with water
(2.times.50 ml), dried (MgSO.sub.4), filtered and concentrated in
vacuo to give a dark oil. The crude residue was purified by flash
chromatography (SiO.sub.2) (1:3--EtOAc:Hexanes) to give the title
compound as a white crystalline solid (0.95 g, 37%). m/z (LC-MSW,
ESP):396 [M+H].sup.+, R/T=4.38 mins.
(iv) 4-(5-aryl-furan-2-yl)-2,6-dimorpholino-pyrimidine derivatives
(66)
[0329] To a solution of
4-(5-bromo-furan-2-yl)-2,6-dimorpholino-pyrimidine (0.03 g, 0.076
mmol) in dioxane (2 ml) were added 2 drops of water, the
appropriate boronic acid (1.2 equiv), tripotassium phosphate (1.2
equiv) and bis(tris-t-butylphosphine)palladium (0.05 equiv). The
reaction vessel was sealed and heated under the influence of
microwave radiation (150.degree. C., 600 s, medium absorption
setting). The reaction was then diluted in EtOAc (5 ml), washed
with water (2 ml) and then brine (2 ml). the organic extract was
removed, filtered through a silica plug, concentrated in vacuo and
purified by preparative HPLC to give the desired compounds.
TABLE-US-00019 Purity m/z RT Compound Ar % [M + H].sup.+ (mins) 66a
##STR237## 95 469.3 8.57 66b ##STR238## 98 453.4 8.56 66c
##STR239## 100 394.3 6.49 66d ##STR240## 100 4223 3.83 66e
##STR241## 97 423.3 4.42 66f ##STR242## 100 409 3.91 66g ##STR243##
99 409.4 4.47 66h ##STR244## 96 489 3.98
Example 14
Synthesis of 4-(4-aryl-thiophen-2-yl)-pyrimidin-2-ylamine
derivatives (69)
[0330] ##STR245## (i) 4-(4-Bromo-thiophen-2-yl)-2-chloro-pyrimidine
(67)
[0331] To a cooled (-78.degree. C.) solution of
2,4-dibromothiophene (1 g, 4.13 mmol) in diethylether (30 ml) was
added n-butyl lithium (2.5M in Hexanes, 4.55 mmol, 1.82 ml). The
solution was maintained at this temperature for 1 hour before the
addition of 2-chloropyrimidine (0.47 g, 4.13 mmol) in a single
portion. The mixture was maintained at -78.degree. C. for a further
1.5 hours before being allowed to warm up to room temperature.
Ethyl acetate (20 ml) was added followed by DDQ (0.94 g, 4.13
mmol). The reaction was stirred for a further 30 minutes before
being concentrated in vacuo. The crude residue was purified by
flash chromatography (SiO.sub.2) (7:3--Hexanes:EtOAc) to give the
desired product (0.42 g, 37%) as a pale yellow solid which
corresponded to the title compound. m/z (LC-MSW, ESP):275
[M+H].sup.+, R/T=4.72 mins.
(ii) 4-(4-Bromo-thiophen-2-yl)-pyrimidin-2-ylamine derivatives
(68)
[0332] A solution of 4-(4-Bromo-thiophen-2-yl)-2-chloro-pyrimidine
(1 equiv, 1.20 mmol) in ethanol (30 ml) was stirred at room
temperature and to this solution was added the appropriate amine (5
equiv). The mixture was heated 70.degree. C. for 16 hours. Upon
cooling the reaction was concentrated in vacuo to give a slurry
which was dissolved in EtOAc (150 ml) and washed with saturated
sodium bicarbonate solution (100 ml). The organic extract was
separated, dried (MgSO.sub.4), filtered and concentrated in vacuo
to give the desired compound in suitably cean form to be used
without any further purification.
[0333] 68a: NRR'=morpholino: m/z (LC-MSW, ESP):326 [M+H].sup.+,
R/T=4.93 mins.
(iii) 4-(4-aryl-thiophen-2-yl)-pyrimidin-2-ylamine derivatives
(69)
[0334] To a solution of the appropriate
4-(4-Bromo-thiophen-2-yl)-pyrimidin-2-ylamine derivative (1 equiv,
0.08 mmol) in 1:1--toluene:Ethanol (5 ml) was added
tetrakis(triphenylphosphine)palladium (0.05 equiv), sodium
carbonate (2 equiv) and the appropriate boronic acid (1 equiv). The
reaction mixture was heated under the influence of microwave
radiation (140.degree. C., 30 minutes, medium absorption setting),
cooled, filtered through a thin silica plug, concentrated in vacuo
and purified by preparative HPLC to give the desired compound.
TABLE-US-00020 Purity m/z RT Compound NRR' Ar % [M + H].sup.+
(mins) 69a ##STR246## ##STR247## 100 400.0 4.31
Example 15
Synthesis of
2-{N-Methyl-N'-[1-Aryl-methylidene]-hydrazino}-pyrido[2,3-d]pyrimidin-4-y-
lamine derivatives (75)
[0335] ##STR248## (i) 1H-Pyrido[2,3-d]pyrimidine-2,4-dione (71)
[0336] A slurry of 2-aminonicotinic acid (10 g, 72.5 mmol),
ammonium chloride (39 g, 725 mmol) and potassium cyanate (30 g, 362
mmol) in water (80 ml) was heated to 80.degree. C. and maintained
at this temperature with stirring for 30 minutes before being
heated to 200.degree. C. The mixture was stirred for 2 hours at
this elevated temperature and then left to cool. Water (200 ml) was
then added and the resultant mixture filtered. The solid was washed
with hot water (100 ml) and then with cold water (2.times.100 ml)
to give a yellow solid which corresponded to the title compound
(11.79 g, 99%) in suitably clean form to be used without any
further purification. m/z (LC-MSW, ESP):164 [M+H].sup.+, R/T=2.11
mins.
(ii) 2,4-Dichloro-pyrido[2,3-d]pyrimidine (72)
[0337] To a solution of 1H-Pyrido[2,3-d]pyrimidine-2,4-dione (5.0
g, 30.65 mmol) in toluene (50 ml), under an inert atmosphere, was
added N,N-diiospropylethylamine (19.81 g, 153.2 mmol). Phosporous
oxychloride (23.50 g, 153.2 mmol) was then added to the mixture
dropwise before the reaction was heated to 100.degree. C. for 3
hours. The mixture was then concentrated in vacuo and then diluted
in CH.sub.2Cl.sub.2 (200 ml) before being poured carefully into ice
water (300 ml). The biphasic mixture was then filtered through a
thin pad of Celite.TM., neutralized and separated. The aqueous
phase was extracted further with CH.sub.2Cl.sub.2 (2.times.100 ml)
and the combined organic extract dried (sodium sulfate), filtered
and concentrated in vacuo to give a thick syrup which was used in
it crude form for the next step.
(iii) 2-Chloro-pyrido[2,3-d]pyrimidin-4-ylamine derivatives
(73)
[0338] Crude 2,4-Dichloro-pyrido[2,3-d]pyrimidine (6.66 g, 33.47
mol) was diluted in anhydrous THF (50 ml) under an inert
atmosphere. To this was slowly added the appropriate amine (0.8
equiv) and the resultant mixture stirred at room temperature for 1
hour. The reaction was concentrated in vacuo and saturated sodium
bicarbonate solution carefully added. The solid was then filtered
and washed with more saturated sodium bicharbonate solution (100
ml) to give the desired compound in suitably clean form to be used
without any further purification.
[0339] 73a: NRR'=morpholino: m/z (LC-MSW, ESP): 251 [M+H].sup.+,
R/T=2.75 mins
(iv) 2-(N-Methyl-hydrazino)-pyrido[2,3-d]pyrimidin-4-ylamine
derivatives (74)
[0340] To a flask charged with isopropyl alcohol (10 ml) was added
the appropriate 2-Chloropyrido[2,3-d]pyrimidin-4-ylamine derivative
(1 equiv, 0.4 mmol) and methylhydrazine (2 equiv, 0.8 mmol). A
reflux condenser was attached and the mixture heated to 50.degree.
C. for 16 hours. The mixture was then cooled (0.degree. C.) and the
resultant precipitate removed by filtration to give the desired
product in suitably clean form to be used without any further
purification.
[0341] 73a: NRR'=morpholino: m/z (LC-MSW, ESP): 261 [M+H].sup.+,
R/T=2.31 mins
(v)
2-{N-Methyl-N'-[1-Aryl-methylidene]-hydrazino}-pyrido[2,3-d]pyrimidi-
n-4-ylamine derivatives (75)
[0342] To a solution of the appropriate
2-(N-Methyl-hydrazino)-pyrido[2,3-d]pyrimidin-4-ylamine derivative
(1 eq, 0.20 mmol)in isopropyl alcohol (5 ml) was added the
appropriate aldehyde (2 eq). Acetic acid was then added until pH 4
was reached. The reaction was heated to 80.degree. C. for 1 hour
whereupon it was cooled and the resultant precipitate collected.
The solid was washed with cold isopropyl alcohol and shown to be
the desired product. TABLE-US-00021 Purity m/z RT Compound NRR' Ar
% [M + H].sup.+ (mins) 75a ##STR249## ##STR250## 99 396.9 3.03 75b
##STR251## ##STR252## 79 424.9 3.22
Example 16
Biological Assay
[0343] For mTOR enzyme activity assays, mTOR protein was isolated
from HeLa cell cytoplasmic extract by immunoprecipitation, and
activity determined essentially as described previously using
recombinant PHAS-1 as a substrate (ref. 21).
[0344] All the compounds tested exhibited IC.sub.50 values less
than 15 .mu.M. The following compounds exhibited an IC.sub.50 less
than 1.5 .mu.M: 5a, 5b, 5l, 5n, 5r, 5t, 12a, 12b, 12h, 171-17c, 27,
29, 36a-36c, 41a, 47a, 50, 53, 59a, 59d-59f, 59i, 59j, 62a,
66a-66h, 69a, 75a, 75b.
REFERENCE LIST
[0345] The following documents are all herein incorporated by
reference. [0346] 1) Brown, et al., Nature, 369, 756-758 (1994)
[0347] 2) Chiu, et al., Proc Nat Acad Sci, 91, 12574-12578 (1994)
[0348] 3) Sabatini, et al., Cell, 78, 35-43, (1994) [0349] 4)
Sabers, et al., J Biol Chem, 270, 825-822 (1995) [0350] 5) Abraham,
Curr Opin Immunol, 8, 412-418 (1996) [0351] 6) Schmelze and Hall,
Cell, 103, 253-262 (2000) [0352] 7) Burnett, et al., Proc Natl Acad
Sci, 95, 1432-1437 (1998) [0353] 8) Terada, et al., Proc Natl Acad
Sci, 91,11477-11481 (1994) [0354] 9) Jeffries, et al., EMBO J, 16,
3693-3704 (1997) [0355] 10) Bjornsti and Houghton, Nat Rev Cancer,
4, 335-348 (2004) [0356] 11) Gingras, et al., Genes Dev, 13,
1422-1437 (1999) [0357] 12) Gingras, et al., Genes Dev, 15, 807-826
(2001) [0358] 13) Neuhaus, et al., Liver Transplantation, 7,
473-484 (2001) [0359] 14) Woods and Marks, Ann Rev Med, 55, 169-178
(2004) [0360] 15) Dahia, Endocrine-Related Cancer, 7, 115-129
(2000) [0361] 16) Cristofano and Pandolfi, Cell, 100, 387-390
(2000) [0362] 17) Samuels, et al., Science, 304, 554 (2004) [0363]
18) Huang and Houghton, Curr Opin Pharmacol, 3, 371-377 (2003)
[0364] 19) Sawyers, Cancer Cell, 4, 343-348 (2003) [0365] 20) Huang
and Houghton, Curr Opin in Invest Drugs, 3, 295-304 (2002) [0366]
21) Brunn, et al., EMBO J, 15, 5256-5267 (1996) [0367] 22) Edinger,
et al., Cancer Res, 63, 8451-8460, (2003) [0368] 23) Lawrence, et
al., Curr Top Microbiol Immunol, 279, 199-213 (2004) [0369] 24)
Eshleman, et al., Cancer Res, 62, 7291-7297 (2002) [0370] 25)
Berge, et al., J. Pharm. Sci., 66, 1-19 (1977). [0371] 26) Green,
T. and Wuts, P., "Protective Groups in Organic Synthesis", 3rd
Edition, John Wiley and Sons (1999) [0372] 27) "Handbook of
Pharmaceutical Additives", 2nd Edition (eds. M. Ash and I. Ash),
2001 (Synapse Information Resources, Inc., Endicott, N.Y., USA),
[0373] 28) "Remington's Pharmaceutical Sciences", 20th edition,
pub. Lippincott, Williams & Wilkins, 2000 [0374] 29) "Handbook
of Pharmaceutical Excipients", 2nd edition, 1994.
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